DNA Topoisomerases

Natassja G Bush; Katherine Evans-Roberts; Anthony Maxwell

doi:10.1128/ecosalplus.esp-0010-2014

. 2015 Apr 17;6(2):10.1128/ecosalplus.ESP-0010-2014. doi: 10.1128/ecosalplus.esp-0010-2014

DNA Topoisomerases

Natassja G Bush ¹, Katherine Evans-Roberts ², Anthony Maxwell ³

Editor: Susan T Lovett⁴

PMCID: PMC11575854 PMID: 26435256

Abstract

DNA topoisomerases are enzymes that control the topology of DNA in all cells. There are two types, I and II, classified according to whether they make transient single- or double-stranded breaks in DNA. Their reactions generally involve the passage of a single- or double-strand segment of DNA through this transient break, stabilized by DNA-protein covalent bonds. All topoisomerases can relax DNA, but DNA gyrase, present in all bacteria, can also introduce supercoils into DNA. Because of their essentiality in all cells and the fact that their reactions proceed via DNA breaks, topoisomerases have become important drug targets; the bacterial enzymes are key targets for antibacterial agents. This article discusses the structure and mechanism of topoisomerases and their roles in the bacterial cell. Targeting of the bacterial topoisomerases by inhibitors, including antibiotics in clinical use, is also discussed.

“Since the two chains in our model are intertwined, it is essential for them to untwist if they are to separate…. Although it is difficult at the moment to see how these processes occur without everything getting tangled, we do not feel that this objection will be insuperable.”

J. D. WATSON AND F. H. C. CRICK

This quotation, taken from the second Watson and Crick paper detailing the structure of DNA (1), predicts a potential problem inherent in the double-helical structure. The processes that utilize DNA, such as transcription, replication, and recombination, require either the temporary or permanent separation of the complementary strands of the double helix. The structure of duplex DNA inevitably leads to topological consequences, such as the introduction of supercoils, during these processes. These changes in topology are resolved by members of a ubiquitous family of enzymes known as DNA topoisomerases (2, 3, 4, 5, 6, 7). Topoisomerases alter DNA topology by binding to the DNA, cleaving either one or both strands of the double helix, then (for most of these enzymes) passing either the other strand of the same helix or another double strand through the break, and finally resealing the DNA backbone. DNA cleavage always involves the formation of a transient phosphodiester bond between one end of the broken strand and a tyrosine in the active site of the topoisomerase. Some topoisomerases require divalent metal ions as cofactors in the DNA cleavage-religation reaction. The reactions performed by DNA topoisomerases are depicted in Fig. 1 and Fig. 2. It should be pointed out that many enzymes (e.g., ligases and recombinases) can affect DNA topology but are not referred to as topoisomerases, which is a term reserved for enzymes whose specific role is manipulation of DNA topology. Similarly, there may be enzymes currently classified as topoisomerases (e.g., topoisomerase III [topo III] and reverse gyrase) whose principal cellular function may be another activity.

**Reactions performed by type I topoisomerases.** Examples of specific type I topoisomerases that catalyze the indicated reactions are given above the arrows. It is important to note that in the decatenation/catenation reaction, the non-nicked plasmid may be supercoiled before decatenation/catenation occurs; for illustrative purposes it has been drawn as relaxed. (Adapted from reference 313 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f1

**Reactions performed by type II topoisomerases.** Examples of specific type II topoisomerases that catalyze the indicated reactions are given above the arrows. It is important to note that in the decatenation/catenation reaction, the plasmids may be supercoiled before decatenation/catenation occurs; for illustrative purposes they have been drawn as relaxed. Although only relaxation of negative supercoils is shown, all known type II topoisomerases can relax positively supercoiled DNA as well. (Redrawn from reference 313 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f2

DNA supercoiling can be either positive (corresponding to over-twisting of the helix) or negative (corresponding to under-twisting of the helix). The binding of proteins to DNA is often dependent on the DNA being negatively supercoiled; initiation of the replication of bacterial plasmids requires negative supercoiling to facilitate the unwinding of the origin sequence (8). As DNA replication proceeds, positive supercoils are generated ahead of the replication fork and so-called precatenanes may build up behind it (Fig. 3) (9). The supercoils are removed by topoisomerases to prevent excess supercoiling and the breakdown of the replication machinery.

**Model of the topology of a replicating chromosome.** The chromosome is separated into domains with the boundaries represented as orange boxes; the replication fork is in the center. Positive supercoiling occurs ahead of the replication fork, and precatenanes may form behind it. (Reprinted from reference 9. Copyright 2001 National Academy of Sciences, U.S.A.) doi:10.1128/ecosalplus.ESP-0010-2014.f3

When two replication forks converge at the end of DNA replication, catenated DNA rings can be formed if the daughter molecules are interwound; i.e., precatenanes are converted to catenanes (Fig. 4) (10, 11). These rings can be separated by decatenation, in which one DNA ring is cleaved and the other ring is passed through the double-strand break. As discussed below, this situation can be resolved by the activities of various topoisomerases.

**Formation of catenated DNA at the termination of replication.** (a and b) Converging replication forks (a) lead to the interwinding of daughter molecules and the formation of precatenanes (b). (c) Upon the completion of replication, the products are catenated DNA circles. (Reprinted from reference 2 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f4

Transcription may also result in changes to DNA topology, for example, if the DNA is anchored to a fixed point in the cell. It has been proposed that during transcription DNA rotates on its axis to allow RNA polymerase to follow the helical path of the DNA strands (12). This rotation leads to the buildup of positive supercoils ahead of the transcription complex and negative supercoils behind it, and in prokaryotes these supercoils can be removed by the enzymes DNA gyrase, topo IV and topo I (11, 13, 14). The transcription of many genes has been shown to be influenced by the level of supercoiling in the bacterial cell (15, 16). This is because supercoiling affects DNA binding by RNA polymerase and other proteins that repress or activate transcription. In fact, the levels of transcription of the genes encoding topo I (topA) and DNA gyrase (gyrA and gyrB) are all affected by the degree of supercoiling, in what is thought to be a homeostatic mechanism to control the amount of supercoiling in the cell (17). Increased negative supercoiling increases the transcription of topA and decreases the expression of gyrA and gyrB. Although its major role is thought to be in decatenation, topo IV has also been shown to participate in supercoiling control by contributing to DNA relaxation (18).

In this article we discuss the structures, roles, and mechanisms of the different topoisomerases. We also describe compounds that inhibit topoisomerases. Although this review focuses mainly on prokaryotic topoisomerases, some details of eukaryotic topoisomerases are also provided for comparison.

CLASSIFICATION OF TOPOISOMERASES

DNA topoisomerases can be divided into two classes: type I topoisomerases introduce transient breaks into DNA single strands, whereas type II enzymes introduce transient double-strand breaks (19). The two types of topoisomerases can be further subdivided into type IA, IB, IC, IIA, and IIB enzymes according to structural, mechanistic, and evolutionary considerations. The properties of the different groups of topoisomerases are listed in Table 1, which summarizes the in vitro activities of the different enzymes. Alignments of the domains of the type I and type II topoisomerases are shown in Fig. 5 and Fig. 6, respectively.

Table 1.

Key properties of different topoisomerases

Topoisomerase		Type	Enzyme structure	No. of DNA strands cleaved	5′ or 3′ bond formed	Proposed mechanism	ATP dependent	Mg(II) dependent	Activities
									Catenation/decatenation	Knotting/unknotting	Relaxation		Supercoiling
									Catenation/decatenation	Knotting/unknotting	−ve^b	+ve^b	−ve	+ve
Topo I	Bacterial	IA	Monomer	1	5′	Strand passage	No	Yes	Yes^c	Yes^c	Yes	No	No	No
Eukaryotic	IB	Monomer	1	3′	Controlled rotation	No	No	Yes^c	Yes^c	Yes	Yes	No	No
Topo II		IIA	Homo-dimer	2	5′	Strand passage	Yes	Yes	Yes	Yes	Yes	Yes	No	No
Topo III		IA	Monomer	1	5′	Strand passage	No	Yes	Yes^c	Yes	Yes	No	No	No
Topo IV		IIA	Hetero-tetramer	2	5′	Strand passage	Yes	Yes	Yes	Yes	Yes	Yes	No	No
Topo V		IB/IC^a	Monomer	1	3′	Controlled rotation	No	No	Unknown	Unknown	Yes	Yes	No	No
Topo VI		IIB	Hetero-tetramer	2	5′	Strand passage	Yes	Yes	Yes	Unknown	Yes	Yes	No	No
DNA gyrase		IIA	Hetero-tetramer	2	5′	Strand passage	Yes	Yes	Yes^d	Yes	Yes	Yes	Yes	No
Reverse gyrase		IA	Monomer	1	5′	Strand passage	Yes	Yes	No	No	Yes	No	No	Yes

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^{^a}

Topo V was originally described as type IB but has been proposed to form a new class (IC).

^{^b}

-ve indicates negatively supercoiled DNA; +ve indicates positively supercoiled DNA.

^{^c}

Possible only if one substrate is nicked or single stranded.

^{^d}

Decatenation by E. coli DNA gyrase is weak.

Type I Topoisomerases

Topo I

Topo I was the first topoisomerase discovered and was originally named ω protein (6, 20). It is found in both prokaryotes and eukaryotes and can relax negative supercoils and catenate and decatenate nicked DNA (21). Bacterial topo I enzymes (e.g., Escherichia coli topo I) are type IA enzymes (Table 1) and can relax only negatively supercoiled DNA. Eukaryotic topo I enzymes are type IB enzymes (Table 1) and can relax both positively and negatively supercoiled DNA; they are evolutionarily and mechanistically distinct from the bacterial enzymes. E. coli topo I is a 97-kDa protein consisting of three domains (22). The first (N-terminal) domain, which consists of 582 amino acids in E. coli, is responsible for cleavage and strand passage and contains the active-site tyrosine at position 319. The next 162 amino acids make up a Zn(II)-binding domain that contains three tetracysteine motifs. The C-terminal third domain, which contains 121 amino acids, is rich in basic amino acids and contributes to substrate binding.

An N-terminal 67-kDa fragment of E. coli topo I was the first type I topoisomerase structure to be solved (22). The structure forms a “base” and a “lid” around a cavity with a diameter of 28 Å, which could accommodate double-stranded DNA. The active-site tyrosine is positioned at the entrance to this cavity. Since then, other structures of type I topoisomerases have been solved, including the structure of the catalytic domain of E. coli topo I in a covalent complex with bound DNA (Fig. 7) (23). Such information is very valuable in terms of the design of new antibiotics (see below).

**Structure of an N-terminal fragment of *E. coli* DNA topoisomerase I in a covalent complex with DNA.** A ribbon representation of the overall structure of the protein is presented, with four subdomains (DI to DIV) shown in different colors. The bound DNA is shown in green as an electron density map. (Reprinted from reference 23 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f7

In the proposed “enzyme-bridging” model of DNA relaxation by topo I, the enzyme cleaves a single strand of DNA and bridges the gap through which the intact strand is passed (22). The clamp then closes around the intact strand, and the cleaved strand is religated. The protein then reopens to release the passed strand and closes again to complete the cycle (Fig. 8). Recent work suggests that the intact strand may bind in the clamp prior to cleavage and then pass through the enzyme-stabilized single-strand break (24).

**Proposed mechanism for *E. coli* topo I.** The enzyme binds DNA (T segment in red, G segment in black; not to scale) and cleaves one strand (active-site tyrosine in purple), forming a 5′-phosphodiester linkage. The complementary strand is passed through the gap and into the central cavity of the enzyme. The light blue circles indicate areas of structural changes during the open conformation of the enzyme. The nick is resealed, and the strand is released. It is possible that the cycle proceeds in reverse with the T segment being passed out of the enzyme rather than in (steps 7 through 1 rather than 1 through 7) (24). (This figure was published in Viard T, de la Tour CB. 2007. Type IA topoisomerases: a simple puzzle? Biochimie **89:**456–467. Copyright © 2007 Elsevier Masson SAS. [314] All rights reserved.) doi:10.1128/ecosalplus.ESP-0010-2014.f8

Mutations in Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) and E. coli topo I enzymes (topA mutations) are generally nonlethal but lead to the acquisition of compensatory mutations in the DNA gyrase genes, gyrA and gyrB (25, 26, 27, 28); however, topA mutations have been shown to lead to cold sensitivity (28). Despite the apparently nonessential nature of topo I, the stabilization of the complex of topo I and cleaved DNA induces the SOS response, leading to cell death (29). There is, therefore, potential to develop antibacterial compounds targeted to topo I (30, 31); indeed, compounds leading to the stabilization of the topo I cleavage complex have been isolated (32).

In contrast to prokaryotic topo I, eukaryotic topo I is capable of relaxing both positively and negatively supercoiled DNA (33). In the proposed mechanism for eukaryotic topo I (originally proposed for vaccinia virus topo I), a single strand of the DNA is broken following DNA binding (34). The 5′-OH of the broken strand can then rotate around the other strand before the break is resealed, in a process known as controlled rotation (35). Human topo I has become a well-established target for anticancer chemotherapy, with camptothecin and analogs being widely used clinically (36).

Topo III

Topo III is a type IA topoisomerase that relaxes and decatenates DNA but also has the ability to cleave and decatenate RNA molecules (37, 38). Topo III is well conserved across evolutionary lineages and is found in prokaryotes, eukaryotes, and archaea, but this discussion is limited to the prokaryotic enzyme. Topo III has significant homology to E. coli topo I, and its crystal structure is also very similar (Fig. 7), with four distinct domains (37, 39). Topo III deletion mutants are viable, so it is thought that the enzyme shares in vivo activities with other topoisomerases (37). A topo III (topB) deletion mutation in a topo IV temperature-sensitive background is lethal (40), which may point to the ability of topo III to decatenate. One difference between the structures of E. coli topo III and topo I is the presence of an additional loop in topo III known as the decatenation loop. Topo I is able to decatenate only singly catenated molecules (21), whereas topo III can unlink multiple catenated dimers (41). This, along with the evidence that the deletion of the loop greatly reduces the decatenation activity, indicates that the decatenation loop provides topo III with the ability to carry out multiple decatenation reactions (41). Although topo III is capable of relaxing DNA, this does not appear to be its primary function in E. coli. It has been shown to be involved in the resolution of precatenanes and in the segregation of chromosomes during replication (40, 42). RecQ helicases are often linked to topo III, and the two types of enzyme may function in cooperation to resolve some recombination intermediates (43, 44, 45, 46); however, they can also function independently of each other in E. coli (42). Topo III is also proposed to have a role in maintaining genome stability with RecQ helicases by resolving stalled and converging replication forks (47), such as in the process illustrated in Fig. 4.

Topo V

Topo V has been described as a type IB topoisomerase (48) as it shows similarities to eukaryotic topo I and can relax negatively and positively supercoiled DNA. However, it is now thought to be a member of its own class of topoisomerases, type IC, based on structural and biochemical analyses (49, 50). The crystal structure of topo V identified a novel fold, and it appears to have a different positioning of the active-site tyrosine, suggesting a different mechanism for the cleavage-religation reaction (50). To date it has been found in only one genus of Archaea (Methanopyrus); it was initially discovered in the hyperthermophile Methanopyrus kandleri (48). Topo V relaxes supercoiled DNA by a controlled rotation/swivel mechanism by nicking one strand on the DNA and allowing the other strand to rotate around it (51). It has been shown to relax around 12 turns of DNA per second (51), as opposed to type IB topoisomerases which relax 19 turns of DNA per second (52). Topo V also has a role in DNA repair (53).

Reverse gyrase

Reverse gyrase is a type IA topoisomerase that is found in thermophilic and hyperthermophilic archaea and eubacteria (54). It was initially discovered in the acidothermophilic archaeon Sulfolobus (55). The enzyme can relax negatively supercoiled DNA, but interestingly, it can also introduce positive supercoils into relaxed DNA in an ATP-dependent manner (56, 57). The crystal structure of reverse gyrase has been determined and reveals the C-terminal domain to resemble a type 1A topoisomerase (58, 59). The N-terminal domain consists of a helicase-like domain (58, 59) that contains an ATP-binding site, and there is evidence that this is the domain that binds DNA (60). If the helicase domain is deleted, relaxation of negative supercoils can take place in the absence of ATP, which is typical of type 1A topoisomerases (61). Accordingly, if the topoisomerase domain is deleted, the remaining helicase domain can unwind DNA transiently in an ATP-dependent reaction. In addition, DNA unwinding has been shown with full-length reverse gyrase (62). It has been proposed that the controlled unwinding of DNA by reverse gyrase ensures that strand passage occurs in the direction of positive supercoiling (62, 63). As positively supercoiled DNA is more likely than negatively supercoiled DNA to be resistant to the harmful effects of high temperature, it is likely that the action of reverse gyrase is an adaptation to the extreme habitat occupied by the hyperthermophilic archaea.

Type II Topoisomerases

Type II topoisomerases occur in both prokaryotes and eukaryotes, and these enzymes show a number of similarities (Fig. 6). Although the main topic of this review is prokaryotic enzymes, it is useful to summarize what we know about the eukaryotic enzymes first so that comparisons can be made.

Topo II

Eukaryotic topo II is a type IIA topoisomerase that can relax both positively and negatively supercoiled DNA in an ATP- and Mg²⁺-dependent manner. It can also catenate and decatenate DNA and has been found in many eukaryotes, including humans (64, 65), Drosophila melanogaster (66), and Saccharomyces cerevisiae (19). Most higher eukaryotes contain two isoforms, termed topo IIα and topo IIβ (67), which appear to be expressed at different times in the cell cycle and in different cell types (68, 69). Topo IIα is found in proliferating cell types, and expression peaks during the G₂ and M phases of the cell cycle. Topo IIβ is found in all cell types, and its expression is constant throughout the cell cycle (70). More recently, it has been found that Topo IIβ might play a role in cell differentiation and tissue development (71). Topo II is required for the condensation, maintenance of structure, and segregation of daughter chromosomes following DNA replication (65, 72), and it has also been linked to chromosome condensation during apoptosis in mammals (73). Many studies have also shown topo II in S. cerevisiae to be cell cycle regulated.

Topo II has homology to DNA gyrase and topo IV (see below). The N-terminal domain of topo II aligns with GyrB and the topo IV subunit ParE (Fig. 6) (74); the C-terminal domain aligns with GyrA and ParC. It is thought that topo II may have evolved following the fusion of the genes encoding the A and B subunits of gyrase (75). One area where topo II, topo IV, and DNA gyrase differ is the C terminus. In DNA gyrase and topo IV, this domain is important mechanistically, whereas in topo II, it is thought to have a regulatory role and includes nuclear localization signals (76). The structure of residues 1 through 1177 (fully active construct) of S. cerevisiae topo II complexed with ADPNP (5′-adenylyl β,γ-imidodiphosphate, a nonhydrolyzable ATP analog) and DNA has been determined by X-ray crystallography (Fig. 9) (77). It shows a homodimer with the N-terminal domains in a domain-swapping conformation (i.e., the subunits wrap around one another). A previous structure of a 92-kDa (residues 410 through 1202) fragment of yeast topo II in a complex with a DNA oligonucleotide (78) revealed that topo II introduces a 150° bend into the bound G segment of DNA. However, it should be noted that the extent of the bend in the co-crystal structure may be influenced by crystal packing and the use of a doubly nicked DNA substrate. The structure of the ATPase domain of yeast topo II, in a complex with ADPNP and the chemotherapeutic agent ICRF-187, has also been published (79). This structure is similar to that of the ATPase domain of GyrB (see below) but has some differences, such as a smaller central cavity (6 Å) that would appear to be unable to accommodate a DNA duplex, in contrast to that seen in the GyrB structure (80).

**Structure of truncated (amino acids 1 through 1177) *S. cerevisiae* topo II bound to DNA and ADPNP.** One monomer is shaded grey, and the other is colored by functional region. WHD is the winged-helix domain, TOPRIM is the topoisomerase-primase domain. The black box indicates the position of ADPNP, and green indicates DNA. (Reprinted from reference 77 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f9

A two-gate mechanism for topo II action, similar to that for DNA gyrase, has been proposed (81, 82). The gate (G) segment of DNA is bound and bent across the dimeric enzyme at the interface between the C-terminal (DNA-binding) domain and the N-terminal (ATPase) domain. The binding of ATP to the ATPase region results in the capture of the transport (T) segment. Hydrolysis of one molecule of ATP to ADP triggers cleavage of the double-stranded G-segment DNA, with a 4-bp stagger between the cuts in the two strands. The T segment passes through the gap in the G segment and into the cavity formed by the two C-terminal domains. Following strand passage, the two ATPase domains rotate around each other, ensuring the unidirectional movement of the T segment. The G segment is religated; following the hydrolysis of the second ATP molecule, the T segment passes out of the enzyme through the bottom gate, and the release of the ADP molecules allows the enzyme to return to its original conformation (77). Note that although this mechanism is generally referred to as a “two-gate” mechanism (83, 84), most type II topoisomerases actually possess three protein interfaces (Fig. 9), the exception being the type IIB enzymes (see below).

Topo VI

Topo VI is an archaeal type IIB topoisomerase that is found in all known archaea but has also recently been found in plants (85, 86, 87) and in the apicomplexan parasite Plasmodium (88). In Arabidopsis thaliana it is involved in endoreduplication (89), while in Plasmodium spp. it is thought to play a role in schizogeny (88). Topo VI is able to decatenate circular DNA and relax both positive and negative supercoils, and it acts as an A₂B₂ heterotetramer (85). Apart from three motifs in the ATPase domain and the topoisomerase-primase (TOPRIM) fold, topo VI shows no obvious sequence homology to other type II topoisomerases and, therefore, is in its own subfamily (type IIB) (85, 90). The structures of the topo VI A subunit (topo VIA) from Methanococcus jannaschii and topo VIB from Sulfolobus shibatae have been resolved (91, 92), as well as the structures of topo VIB in a variety of conformations involving a range of nucleotides (91, 93). More recently, however, the structure of intact topo VI from Methanosarcina mazei has been determined by using a combination of X-ray crystallography and X-ray scattering analysis (94, 95). From these structures it is evident that one major difference between the A subunit structure of topo VI and those of other type II topoisomerases is the lack of a post-strand passage cavity (i.e., it has only two protein interfaces, rather than the three found in type IIA topoisomerases) (92, 94). Another difference is that the double-stranded breaks made by topo VI have a 2-bp stagger in contrast to the 4-bp stagger created by the type IIA topoisomerases (96). The A subunit of topo VI is homologous to a protein called Spo11, which is ubiquitous in eukaryotes and is involved in initiating homologous recombination during meiosis by cleaving DNA. In this sense, Spo11 is similar to a topoisomerase that does not religate the DNA after cleavage (97). The B subunit of topo VI binds and hydrolyzes ATP, and the ATPase region shows structural similarity to the ATPase regions of the type IIA topoisomerases, despite the largely limited sequence homology. The structural work on the topo VIB subunit has revealed a detailed outline of the nucleotide hydrolysis events and the associated protein conformational changes (91, 93). It is likely that other topo II enzymes go through a similar series of events. Overall, the structures of topo VI have given valuable insights into the mechanism of strand passage by this enzyme and other topoisomerases.

Very recently a new type IIB enzyme, topo VIII, in which the A and B subunits are fused into a single polypeptide, has been reported (98). Topo VIII occurs in several bacterial genomes and bacterial and archaeal plasmids. It is the smallest known type IIB enzyme and could be a promising model for future structural and mechanistic studies.

Topo IV

Topo IV is a bacterial type IIA enzyme that uses the hydrolysis of ATP (99) to decatenate replication products (100), relax positive and negative (although less efficiently) supercoils (101), and knot and unknot DNA (102, 103). E. coli and Salmonella Typhimurium topo IV consists of two subunits, encoded by the parC and parE genes, which form a heterotetramer (99); in a few other organisms (e.g., Staphylococcus aureus, Oceanobacillus iheyensis, and Macrococcus caseolyticus), the corresponding genes are termed grlA and grlB (104, 105, 106). The ParC subunit (84 kDa in E. coli) and the ParE subunit (70 kDa) are homologous to GyrA and GyrB, respectively (Fig. 6). However, topo IV does show some structural differences from DNA gyrase; unlike gyrase, it is unable to introduce negative supercoils into DNA (107). Topo IV is also around 100 times more active at decatenation in vivo in E. coli cells than is DNA gyrase (11). Although topo IV, and not gyrase, is responsible for decatenation in vivo, gyrase mutants have problems decatenating their chromosomes. This finding implies that DNA compaction by gyrase is necessary for the action of topo IV (108), and, indeed, one of the roles for gyrase (see below) can be viewed as supercoiling DNA catenanes to make them better substrates for topo IV. Further to this, topo IV has been shown to be processive on positively supercoiled DNA but distributive on negatively supercoiled DNA. Positively supercoiled DNA (having left-handed crossings) often occurs ahead of replication forks while right-handed crossings (negatively supercoiled DNA) are often associated with precatenanes and catenated DNA (8, 101, 109, 110, 111). DNA replication is stopped more quickly as a result of mutations in both topo IV and gyrase than as a result of a mutation in gyrase alone (9). Therefore, it seems that despite their sequence similarities, gyrase and topo IV have quite distinct cellular roles. Topo IV has the predominant role in decatenation (and unknotting), whereas gyrase is the only supercoiling enzyme (11, 102, 108, 112). Topo IV also plays a major role in chromosome segregation after DNA replication with the help of motor proteins and cytoskeletal components (5, 113).

The structure of a 43-kDa N-terminal fragment of ParE, in a complex with an ATP analog, has been resolved (114). This structure (Fig. 10) shows significant similarity to that of the corresponding region of GyrB (see Fig. 11). The structure of this domain gives important insight into the mechanism of ATP hydrolysis and the actions of the aminocoumarin antibiotics, which also bind to this region of the protein (see below).

**Structures of topoisomerase IV.** (A) Structure of the ParE-ParC55 fusion construct (122) (PDB: 4I3H). Yellow indicates the GHKL domain, orange is the transducer domain, teal is the winged-helix domain (WHD), purple is the tower domain, and blue shows the coiled-coil domain (see Fig. 6 for domain structure). (B) Space-filled model of the structure shown in panel A. (C) ParE 43-kDa N-terminal fragment complexed with ADPNP (black box) (PDB: 1S16) (114). It is proposed that the open conformation of ParE as seen in panel A is the conformation pre-ATP binding whereas the conformation seen in panel C is the post-ATP-binding conformation. (D) ParC C-terminal domain in two orientations (PDB: 1ZVT) (115). doi:10.1128/ecosalplus.ESP-0010-2014.f10

Structures of full-length E. coli ParC and the ParC C-terminal domain (from Bacillus stearothermophilus) have also been published (115, 116). The full-length ParC structure resembles those of fragments of GyrA and yeast topo II (81, 117, 118) (Fig. 10). One of the main structural differences between gyrase and topo IV is in the C-terminal domains of GyrA and ParC. The GyrA C-terminal domain forms a six-bladed β-pinwheel (see Fig. 11) (119); the structure of the C-terminal domain of ParE consists of a broken five-bladed β-pinwheel (Fig. 10) (115). The C-terminal domain of topo IV is anchored to the N-terminal domain, which would appear to allow only minimal movement of the domain. In contrast, the C-terminal domain of DNA gyrase is connected to the N-terminal domain by a flexible linker, allowing movement (119, 120). This distinction means that topo IV cannot wrap DNA in the same way as DNA gyrase can, providing an explanation for the inability of topo IV to negatively supercoil DNA. Indeed, the deletion of the wrapping domain of gyrase converts it into a topo IV-like enzyme (121). More recently, a ParE-ParC55 structure of Streptococcus pneumoniae topo IV has been resolved (122). This structure, which consists of a fusion of the full-length ParE subunits and the N-terminal domain of ParC (ParC55) subunits, shows the ParE ATPase domains lying back in an open conformation and linked to the TOPRIM domain by a flexible joint (Fig. 10). This open conformation is thought to show the enzyme conformation prior to DNA binding.

DNA gyrase

DNA gyrase is a type IIA topoisomerase that is unique in its ability to introduce negative supercoils into covalently closed double-stranded DNA in the presence of ATP (123). It also uses ATP hydrolysis to relax positively supercoiled DNA in a reaction equivalent to the introduction of negative supercoils, despite this process being energetically favorable (124, 125). It has also been shown to be capable of decatenation and unknotting reactions in the presence of ATP; it is also presumably capable of catenation and knotting reactions (19, 126, 127, 128). Furthermore, DNA gyrase can relax negatively supercoiled DNA in an ATP-independent reaction (129, 130). DNA gyrases are ubiquitous in bacteria; however, E. coli DNA gyrase has been the most intensively studied. E. coli DNA gyrase is made up of two 97-kDa GyrA subunits and two 90-kDa GyrB subunits encoded by the gyrA and gyrB genes, respectively, and organized as an A₂B₂ heterotetramer (131, 132, 133, 134). DNA gyrases have also been discovered in plants (135, 136) and in apicomplexan parasites (137, 138) but do not appear to be present in other eukaryotes. This, along with the fact that DNA gyrase is an essential bacterial enzyme, has made it a successful target for several antibacterial agents.

Structure of DNA gyrase

The GyrA and GyrB subunits each consist of two principal domains, as revealed by limited proteolysis (Fig. 6) (139, 140). E. coli GyrB comprises a 43-kDa N-terminal domain responsible for ATP binding and hydrolysis (80, 141) and a 47-kDa C-terminal domain that interacts with GyrA and DNA (141, 142, 143, 144). The 47-kDa domain of GyrB may be further subdivided into two subdomains, the TOPRIM domain and the tail (145, 146). E. coli GyrA consists of a 59-kDa N-terminal domain responsible for DNA breakage (147) and a 35-kDa C-terminal domain that wraps DNA. The 59-kDa domain can be further divided into the tower/shoulder, winged-helix, and coiled-coil domains in line with other type IIA topoisomerases (i.e., the C-terminal domain in topo II and ParC in topo IV) (78, 81, 118, 148). The 35-kDa domain is essential for the ability of DNA gyrase to negatively supercoil DNA (121, 149), and its deletion converts gyrase into a conventional (DNA-relaxing) enzyme like topo IV (121, 150).

The protein structures of all the gyrase domains have been resolved. The first gyrase domain structure to be determined was that of the E. coli GyrB 43-kDa N-terminal domain in a complex with ADPNP (80). The structure is a dimer (Fig. 11); each monomer consists of an N-terminal ATP-binding site (amino acids 2 to 220) and a C-terminal portion that forms the walls of a central ∼20-Å cavity, potentially large enough to hold a DNA duplex (151). The N-terminal portion contains the residues involved in dimer contacts (amino acids 2 to 15) and also four motifs conserved in members of the GHKL ATPase/kinase superfamily of proteins (152). Two residues in the C-terminal portion (Q335 and K337) have been shown to interact with ATP (153). The central cavity formed by the C-terminal portion is lined with positively charged arginine residues. Mutagenesis studies revealed that at least one of these residues is important for DNA binding and strand passage (151).

The structure of the GyrB C-terminal domain has been solved from E. coli and Mycobacterium tuberculosis DNA gyrase (144, 146, 154). These structures were also shown to be dimers forming a “crab-like” structure with the globular TOPRIM domains forming the “body” and the tail domains extending out to appear “claw-like.” The domains are linked by a loop-helix-loop region. The TOPRIM domain contains three acidic residues (E459, D532, and D534) responsible for binding the magnesium ion necessary for the cleavage-religation reaction. These residues are highly conserved among DNA gyrases (144, 146, 154). The E. coli GyrB C-terminal domain differs from the M. tuberculosis structure by a 170-amino-acid insert which adopts an extended fold. This lies alongside the coiled-coil domain of the GyrA subunit (Fig. 11). This extra insert is thought to have a role in DNA binding and DNA-stimulated ATPase activity (142, 144).

The structure of the 59-kDa N-terminal domain of E. coli GyrA was resolved in 1997 (118). This structure is also a dimer and contains a 30-Å central cavity (Fig. 11). There are two dimer interfaces, at the top and bottom of the structure, which comprise the DNA gate and the C-gate, respectively. The interface at the top of the dimer contains the active-site tyrosines, which form phosphotyrosine bonds with the 5′ ends of the broken DNA. The region across the dimer interface at the top of the domain provides a positively charged saddle, which is proposed to promote DNA binding.

The structure of the 35-kDa C-terminal domain of DNA gyrase from a number of bacterial species, including Borrelia burgdorferi, E. coli, M. tuberculosis, and Xanthomonas campestris, has been determined (119, 155, 156, 157). This domain forms a six-bladed β-pinwheel (Fig. 11) in which each β-strand backs against and completes the previous blade of the structure. The outer two-thirds of the surface of the structure is basic in charge, suggesting that this region may be involved in the binding and bending of DNA. Although they all share this basic structure, they have slight structural differences; e.g., the E. coli, X. campestris, and M. tuberculosis GyrA C-terminal domains have a spiral shape, unlike the B. burgdorferi structure, which is flat. Another important structural feature of the C-terminal domain is the 7-amino-acid motif called the GyrA-box (158, 159). This motif is crucial to supercoiling activity and is found on a loop between blades 1 and 6 (158, 160).

No high-resolution structures of the whole DNA gyrase enzyme have been presented to date. However, low-resolution structures of the entire GyrA protein and the GyrB protein have been determined using small-angle X-ray scattering (SAXS) (120, 145, 161). A GyrB-A fusion structure has also been elucidated by supramolecular mass spectrometry and 3D cryoelectron microscopy (cryo-EM) (162). Recently, a number of GyrB-A fusion structures with DNA and a quinolone drug bound have been resolved by X-ray crystallography (see below), as well as structures with topo IV, DNA, and drugs (163, 164, 165).

Ab initio modeling shows the 59-kDa N-terminal domain forming a dimeric core, with a pear-shaped density pattern on either side. These densities may accommodate the crystal structure of the GyrA C-terminal domain (119) attached to the N-terminal domain by a flexible linker. The cryo-EM structures complexed with ADPNP, ciprofloxacin, and DNA indicate that the GyrA C-terminal domains are elevated, alongside the DNA gate and GyrB subunits (Fig. 12) (162). The molecular envelope of GyrB has a “tadpole” shape, with the ATPase domain structure of GyrB (80) fitting into the head of this envelope and the remainder being made up of the TOPRIM fold (81) and the tail subdomains. Investigation by analytical ultracentrifugation has revealed that GyrB, unlike GyrA, is predominantly a monomer in solution (120, 145). The structural information from topo II structures (81) implies that GyrB sits above GyrA in the complex (Fig. 9). This is corroborated by the SAXS and cryo-EM data, which imply that the GyrB ATPase domains are positioned above the DNA cleavage active site at an angle between 60 and 105° (161, 162). The data also suggest the ATPase domain is angled 15 to 20° toward one of the GyrA C-terminal domains (162).

**Cryo-EM map of the DNA-bound complex modeled with the crystal structures of DNA gyrase domains alone (A) and with duplex DNA (B).** In particular, the crystal structures of the ATPase (PDB:1EI1) and the DNA-binding-cleavage domain in the presence of ciprofloxacin (PDB:2XCT) were modeled into the core of the map with the two additional densities on both side of the core enzyme accommodating the C-terminal domains (PDB:3L6V). (Reprinted from reference 162 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f12

Mechanism of action of DNA gyrase

Biochemical characterization of the roles of GyrA and GyrB has revealed details of the mechanism of supercoiling by gyrase. More recently, single-molecule experiments have corroborated this biochemical data and further extended our knowledge and understanding of this mechanism.

Negative supercoiling occurs via a two-gate mechanism (128) (Fig. 13). A section of DNA termed the gate or G segment binds across the top dimer interface of the GyrA N-terminal domains (118, 133). Upon binding, the G segment is bent at an angle of about 70°, which is much less than in the S. cerevisiae topo II structure (78, 162). Binding of the G segment induces an upward movement of the GyrA C-terminal domains, resulting in an adjacent section of the DNA becoming wrapped around the C-terminal domain (166, 167). This wrapping positions a further DNA section, termed the transport or T segment, across the G segment at an angle of about 60° (162, 166). The GyrA box is thought to ensure the orientation of the T segment in a way that favors DNA supercoiling (158, 159, 160). This wrapping by the GyrA C-terminal domain provides gyrase with its unique ability to supercoil DNA (119, 149, 156). The total length of DNA bound by gyrase is estimated to be between 120 and 150 bp (168, 169, 170, 171, 172). DNA binding has also been shown to induce narrowing of the GyrB N-terminal domains (173). DNA wrapping and the presentation of the T segment has been demonstrated to occur in the absence of ATP; however, ATP (or ADPNP) is crucial for strand passage to occur (174). Following DNA binding and wrapping, ATP is bound to the N-terminal domains of the two GyrB subunits, resulting in their dimerization and the closure of the clamp. This closure traps the T segment in the complex (174, 175). In E. coli a small acidic tail on the GyrA C-terminal domain has been implicated in the coupling of ATP to DNA wrapping, thus controlling supercoiling (176).

**Model for negative supercoiling by DNA gyrase.** The domains are colored as follows: GyrB43, dark blue; GyrB TOPRIM, red; GyrB tail, green; GyrA59, orange; GyrA C-terminal domain, light blue. The G and T DNA segments are colored black and purple, respectively. 1, subunits and DNA in their proposed free states in solution. Stars indicate the active-site residues for DNA cleavage, and the circle indicates the ATP-binding pocket. 2, The G segment binds across GyrA at the dimer interface, and the GyrA C-terminal domain wraps the DNA to present the T segment in a positive crossover. 3, ATP is bound, which closes the GyrB clamp capturing the T segment, and the G segment is transiently cleaved. 4, Hydrolysis of one ATP molecule allows GyrB to rotate, the DNA gate to widen, and the T segment to be transported through the cleaved G segment. 5, The T segment exits through the C gate, and the G segment is religated. The hydrolysis of the remaining ATP molecule resets the enzyme. The right panel shows the side view for illustrations 2 through 4. (Reprinted from reference 145 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f13

The active-site tyrosines form phosphotyrosine bonds with the G segment, generating a double-strand break with 4-bp overhangs (147, 171). Two Mg²⁺ ions bound within the TOPRIM fold of GyrB are required for the cleavage of the DNA strands (143). The top dimer interface is pulled apart, and with it the G segment, allowing the T segment to pass through into the cavity formed by the GyrA N-terminal domains. The GyrA cavity carries a positive charge and so provides a favorable environment for DNA (118).

The G segment is religated, and the T segment is released through the bottom gate of the GyrA N-terminal domains. It is not currently clear what drives the movement of the T segment at this stage. It has been proposed that it may be the closure of the top gate, which makes the GyrA cavity smaller (177). More recently it was proposed that the closing and swiveling observed in the GyrB subunits may ensure unidirectional movement of the T segment (162, 173). The rotating of the N-terminal domains (GyrB equivalent) in S. cerevisiae has also been shown in its crystal structure (77).

ATP hydrolysis allows the resetting of the enzyme (125); ADPNP is sufficient for the capture of the T segment (83, 178, 179, 180) and for a single strand-passage reaction to occur, but the enzyme is then trapped in an inactive state (125, 181). More detailed studies of the interaction of ADPNP with gyrase have provided evidence of the cooperative role of the two ATP-binding sites in the supercoiling cycle and examined the coupling of nucleotide binding to strand passage at different levels of supercoiling (182, 183). To date, the mechanism that drives ATP hydrolysis is uncertain; however, the ATPase activity has been revealed to be stimulated by cleaved DNA in the presence of GyrA (184). It has been proposed that the rate-limiting aspect of the DNA supercoiling reaction is the rate of ADP and phosphate release (178, 185). The coupling of supercoiling to ATP binding/hydrolysis has received significant attention, and it seems that gyrase-catalyzed ATPase activity is not tightly coupled to supercoiling; as gyrase goes through a supercoiling reaction, ATP continues to be hydrolyzed at a high rate, even after the enzyme has reached the supercoiling endpoint (125, 182, 183). It should be noted that Fig. 13 suggests that the two ATPs may be hydrolyzed sequentially in the supercoiling mechanism; this is based on work carried out with yeast topo II (186) and may not necessarily apply to gyrase. Indeed, work on gyrase suggests that ATP binding may be sufficient to carry out a complete strand passage reaction (ΔLk – 2) without hydrolysis (125, 182, 183), which may be required only to reset the enzyme. However, it is also worth noting that gyrase can carry out limited catalytic supercoiling with the binding and hydrolysis of only one ATP (187). The full intricacies of the gyrase supercoiling reaction and the coupling of ATP binding/hydrolysis are still under active investigation.

DNA gyrase can also relax negatively supercoiled DNA, which occurs as the reverse of the reaction described previously, with the T segment passing through the enzyme in the opposite direction (188). This reaction is ATP independent, since it is energetically favorable, and is far less efficient than the supercoiling reaction (129, 130). DNA gyrase can also relax positively supercoiled DNA. This reaction occurs in the same way as negative supercoiling and requires ATP, even though it is energetically favorable (141). The catenation-decatenation and knotting-unknotting reactions performed by gyrase are also ATP dependent (19, 126).

DRUGS AND TOXINS THAT TARGET BACTERIAL DNA TOPOISOMERASES

DNA topoisomerases are important targets for antimicrobial drugs (31). DNA gyrase is essential for the survival of bacteria but is largely absent in eukaryotes and is therefore an ideal drug target. DNA topoisomerase I is regarded as nonessential, but the fact that its mechanism involves the formation of a cleavage complex with DNA raises the possibility of exploiting this target. At the time of writing, there are no commercially produced antibacterial agents that target topo I, but there is ongoing work to find such agents. Topo I and gyrase are discussed separately.

Topo I

Although bacterial topo I appears to be nonessential, the discovery of compounds that stabilize the cleavage complex and show antibacterial activity raises the possibility of new antibacterials targeted to topo I in the future (30). Proof of principle for this assertion has been provided by experiments in which a mutant form of Yersinia pestis topo I that forms a stabilized covalent complex was shown to result in cell death in E. coli (29). Subsequently it was shown that compounds that enhance DNA cleavage by topo I have antibacterial activity (32). More recently 3,4-dimethoxyphenyl bis-benzimidazole has been shown to target E. coli topo I and to have low MICs for a range of E. coli strains (189). Taken together, it seems likely that clinically relevant compounds that target bacterial topo I will be available in the future.

DNA Gyrase

At the moment the only bacterial topoisomerase target that is commercially significant is DNA gyrase, although a number of gyrase-targeting agents also target the sister enzyme topo IV. There are two well-known classes of drugs that target gyrase: the aminocoumarins and quinolones (190). The quinolones are synthetic, whereas the aminocoumarins are products of Streptomyces species (Table 2).

Table 2.

Inhibitors of DNA gyrase

Drug(s) or toxin	Source	Mode of action
Aminocoumarins (e.g., novobiocin)	Streptomyces species	Competitive inhibition of ATP binding
Quinolones (e.g., ciprofloxacin)	Synthetic	Stabilization of DNA cleavage complex
Albicidin	Xanthomonas albilineans	Stabilization of DNA cleavage complex
Simocyclinones (e.g., simocyclinone D8)	Streptomyces antibioticus	Prevention of DNA binding
MccB17	Escherichia coli	Stabilization of DNA cleavage complex
CcdB	Escherichia coli	Stabilization of DNA cleavage complex

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Aminocoumarins

The aminocoumarins are more potent inhibitors of gyrase than are the quinolones in vitro, but their low solubility and toxicity in eukaryotes make them less useful clinically (190). These compounds are produced by Streptomyces species and include novobiocin, clorobiocin, and coumermycin A₁ (Fig. 14) (191, 192, 193, 194, 195, 196, 197).

Aminocoumarins inhibit supercoiling, leading to the identification of DNA gyrase as the target (124). However, the aminocoumarins do not inhibit ATP-independent relaxation (198, 199), consistent with their being competitive inhibitors of ATP hydrolysis. This conclusion is supported by work showing that novobiocin strongly inhibits the gyrase ATPase reaction, which is relatively unaffected by the quinolone oxolinic acid (200). Aminocoumarin-resistant strains of E. coli frequently contain a mutation of Arg¹³⁶ (201, 202), a residue not directly implicated in ATP binding (80). This discrepancy was explained with the resolution of crystal structures of the N-terminal 24-kDa subdomain of GyrB in complexes with novobiocin and clorobiocin (203, 204, 205); the structure of the corresponding region of E. coli ParE (topo IV) in a complex with novobiocin has also been determined (114). Indeed, topo IV is a secondary target of novobiocin (206). There is only a partial overlap between the aminocoumarin drugs and ATP-binding sites, with the novobiose sugar of novobiocin overlapping with the adenine ring of ATP (Fig. 15). Novobiocin forms a hydrogen bond with Arg¹³⁶ and has been shown to prevent the dimerization of the 43-kDa GyrB N-terminal domains (178, 204).

**The binding sites of novobiocin and ADPNP in GyrB partially overlap.** Part of the N-terminal GyrB structure is shown, with ADPNP in red and novobiocin in blue (204). doi:10.1128/ecosalplus.ESP-0010-2014.f15

The biosynthetic gene clusters for novobiocin, coumermycin A₁, and clorobiocin have been cloned and sequenced (207, 208, 209, 210). All three clusters contain a gene encoding an aminocoumarin-resistant GyrB subunit, and the clorobiocin and coumermycin A₁ gene clusters also encode a ParY subunit, encoding a drug-resistant subunit (ParE) of topo IV (207). Differences among the gene clusters for these compounds correspond to differences in the compound structures; for example, novobiocin contains a methyl group at position 8 on the aminocoumarin ring, and its biosynthetic gene cluster contains novO, a C-methyltransferase gene (207). Clorobiocin contains a chlorine atom at position 8 on the ring, and the corresponding gene (clo-hal) in the clorobiocin gene cluster has similarity to a reduced flavin adenine dinucleotide-dependent halogenase gene. The replacement of the clo-hal gene in the clorobiocin gene cluster with novO results in an 8′-methylated derivative (211). Modification of the aminocoumarin gene clusters by genetic engineering therefore has the potential to generate novel antibiotics. For example, analogs of novobiocin and clorobiocin, termed novclobiocins, have been generated (212, 213). Although most of these analogs are less potent than the parent molecules, novobiocin and clorobiocin, some show equal or even greater potency. Moreover, many of the analogs have improved physicochemical properties and present the possibility of developing superior chemotherapeutic agents.

Simocyclinones

Simocyclinones D4 and D8 (Fig. 16) are gyrase-inhibiting antibiotics from Streptomyces antibioticus (214, 215). It was noted that some of the genes in the simocyclinone cluster have similarities to those in the aminocoumarin gene cluster, and the simocyclinone structure includes an aminocoumarin moiety (216, 217).

Structure of simocyclinone D8. doi:10.1128/ecosalplus.ESP-0010-2014.f16

Simocyclinone D8 (SD8) has been shown to be a potent inhibitor of both the supercoiling and relaxation activities of gyrase in vitro (218). Despite the similarities between SD8 and the classical aminocoumarins, they show key differences in their modes of action. SD8 does not competitively inhibit the ATPase reaction, nor does it stabilize the gyrase-DNA cleavage complex like the quinolones (218); instead, it acts at an early stage in the gyrase catalytic cycle to prevent DNA binding (218, 219). The first crystal structure of SD8 bound to the N-terminal domain of E. coli GyrA showed that both ends of the molecule interact with the protein, leading to its being dubbed a “double-headed antibiotic” (219). This crystal structure has been more recently refined by mass spectrometry studies (220) and subsequent X-ray crystallography (221), showing that a single SD8 molecule can bridge both binding pockets in a single GyrA protomer (Fig. 17).

Figure 17a — **Structure of the N-terminal domain of GyrA (GyrA55) complexed with simocyclinone D8.** The protein dimer is shown in gold and blue (ribbon representation), and the bound simocyclinone D8 dimer is shown in space-filling representation. (A) Side view. (B) Top view. Note that the polyketide end of each simocyclinone molecule also binds to the other monomer across the dimer (DNA-gate) interface (221). doi:10.1128/ecosalplus.ESP-0010-2014.f17a

Although SD8 is an effective inhibitor of E. coli gyrase, it is ineffective against gram-negative bacteria and is active against only certain gram-positive organisms (215, 222). Simocyclinones are not particularly promising as drug candidates as a result of their lack of penetration into bacteria and also on account of their low solubility and toxicity in eukaryotes (215, 223), but it is hoped that modification of the structure may circumvent these problems. In particular, their novel mode of action suggests that there are still further unexploited strategies for inhibiting bacterial gyrase.

Quinolones

The quinolones are the most therapeutically important class of DNA gyrase inhibitors, and they have been used to treat a wide range of infections (190, 224, 225, 226). The quinolones traditionally have been divided into two categories: the older acidic quinolones, such as nalidixic acid, which act against gram-negative bacteria, and the amphoteric fluoroquinolones, such as ciprofloxacin (Fig. 18); strictly speaking, nalidixic acid is a naphthyridone, not a quinolone, but is usually grouped with the quinolone drugs. More recently, the quinolones have been classified in terms of the evolution of their structures and clinical indications: narrow-spectrum drugs include nalidixic acid; expanded-spectrum drugs include norfloxacin and ciprofloxacin; broad-spectrum quinolones include levofloxacin and sparfloxacin; and “fourth-generation” drugs include trovafloxacin (227). With the increased spectrum seen in the newer generations of the fluoroquinolones, there has also been an improvement in the bioavailability of these drugs, as well as better tissue penetration and improvements in safety and tolerability (227).

The quinolones have been shown to inhibit DNA supercoiling and relaxation by binding to both gyrase and DNA and stabilizing the formation of the gyrase-DNA cleavage complex (198, 199). In recent years the specifics of the interaction between quinolones and the gyrase-DNA complex have been revealed by X-ray crystallography (see below). The inhibition of DNA synthesis by quinolones is due not to the inhibition of gyrase activity per se but to the quinolone-gyrase-DNA complex blocking the DNA replication machinery and hence blocking cell growth (228, 229, 230). This effect is likely to result in the bacteriostatic action of quinolones (231). Cell death is likely to be due to DNA breaks, which form a second step in the process and can occur by both protein synthesis-dependent and -independent routes (231, 232). DNA replication is stopped rapidly when DNA gyrase is targeted with quinolone drugs, apparently due to the collision of replication forks with cleaved complexes (233). For example, norfloxacin has been shown to cause stalled replication forks in vivo; however, this inhibition cannot be the immediate cause of cell death, as it is reversible (234, 235). Also, bacteria in which DNA replication has been inhibited can subsequently be killed by treatment with nalidixic acid or ciprofloxacin (236). The inhibition of DNA replication by quinolones results in the induction of the SOS regulon in a RecBC-dependent manner (237). One of the genes induced is an inhibitor of cell division, so the SOS response results in cell filamentation, which may lead to the slow death of the cell (238). The release of DNA with double-strand breaks from several cleavage complexes may cause chromosome fragmentation and leads to rapid cell death (239). Chromosome fragmentation may be dependent on or independent of protein synthesis. Protein synthesis-dependent chromosome fragmentation is inhibited by chloramphenicol, and it has been proposed that a suicide factor is involved (232, 240). There is evidence to support the idea that the RecB and RecC proteins are involved in nalidixic acid-induced breaks (241). The MICs of quinolones are 10- to 100-fold lower (in vivo) than their 50% inhibitory concentrations (IC₅₀s) (in vitro) (198, 242). This property can be explained by a low concentration of the inhibitor in vivo triggering the downstream responses that lead to cell death. In bacteria, susceptibility to quinolones is always dominant over resistance, as the presence of double-strand breaks is lethal.

Quinolone-resistant strains of bacteria are being increasingly reported (243, 244). Some of these strains are deficient in the uptake of the drug, but many have mutations in gyrase itself. In addition to the gyrase mutations, some strains have mutations in topo IV, a secondary target for quinolones in some bacteria (245) and the primary target in others, such as Staphylococcus aureus (105, 246, 247). The mutations in gyrase that confer resistance to quinolones are often found between amino acids 67 and 106 of GyrA (E. coli numbering). This region of the subunit has been termed the quinolone-resistance-determining region (QRDR) (248). The mutations cluster at the head-dimer interface, near the active-site tyrosines (118); mutations conferring quinolone resistance have also been found in the corresponding region of topo IV (249). Although most quinolone resistance mutations in gyrase occur in GyrA, mutations in GyrB have also been found, in both E. coli and Salmonella Typhimurium (250, 251, 252).

The residues most commonly mutated in ciprofloxacin-resistant strains are Ser⁸³ and Asp⁸⁷ in GyrA (248); corresponding mutations in Salmonella Typhimurium have also been found (253, 254). Both of these residues are in close proximity to the active-site tyrosine, and mutations of these residues are thought to reduce quinolone binding (255). Resistance-conferring mutations outside the traditional QRDR have also been identified. For example, an Ala⁵¹-to-Val mutation results in a sixfold increase in ciprofloxacin resistance (256). Mutations of Asp⁴²⁶ or Lys⁴⁴⁶ of GyrB have also been shown to result in quinolone resistance (252, 257). It appears that these residues may be close to the active-site tyrosine and thus may form part of the quinolone-binding pocket (258). With the advent of crystal structures of quinolones bound to gyrase-DNA and topo IV-DNA complexes, the quinolone resistance mutations can now be better rationalized. Structures exist of a large fragment of Streptococcus pneumoniae topo IV complexed with DNA and moxifloxacin and clinafloxacin (165), Staphylococcus aureus gyrase complexed with DNA and ciprofloxacin (164), and Acinetobacter baumannii topo IV complexed with DNA and moxifloxacin (163). In all cases the structure includes DNA, emphasizing the importance of DNA in the quinolone complex. Also, the structures do not include complete subunits, but it appears that the drug-binding pockets are fully represented. In these structures the aromatic rings of the quinolones are stacked against the DNA base pairs at the site of cleavage, and interactions of the drug with residues from both subunits are observed (Fig. 19).

**Topo IV-DNA-quinolone complex.** (a) ParE28-ParC58 is a fusion of the C-terminal region of ParE and the N-terminal region of ParC. (b) ParE28-ParC58 complex with DNA (green), moxifloxacin (yellow carbons), and Mg²⁺ ions (orange spheres). One fused ParE-ParC subunit is shown in red-blue; the other is all gray. (Reprinted from reference 163 with permission of the publisher.) doi:10.1128/ecosalplus.ESP-0010-2014.f19

In addition to the quinolone resistance mutations found in gyrase, some clinical strains have plasmid-borne resistance to quinolones (259). This resistance turns out to be due to pentapeptide repeat proteins, Qnr in E. coli and MfpA in Mycobacterium tuberculosis (260), which can bind gyrase and inhibit its activity (see below).

Microcin B17

Aside from the range of drugs and small molecules that target gyrase, there are a number of bacterial toxins that can also inhibit gyrase activity. One of these is microcin B17 (MccB17) (Fig. 20), which is a glycine-rich peptide found in strains of E. coli containing the plasmid-borne mcb operon. It induces double-strand cleavage of DNA by gyrase and inhibits DNA synthesis, and its action results in cell death (261, 262). MccB17 acts by stabilizing the gyrase-DNA cleavage complex in a way similar to quinolones, and like the quinolones, it does not require ATP (263, 264); however, the presence of ATP greatly enhances the effect of MccB17 (it is ca. 10 times more active with ATP) (264). MccB17 requires at least 150 bp of DNA to induce the formation of cleavage complexes; however, the DNA-wrapping domain of GyrA is not required, nor is the ATPase domain of GyrB (265). MccB17 is therefore likely to interact with the N-terminal domain of GyrA, the C-terminal domain of GyrB, and DNA. Mutation of the amino acid Trp⁷⁵¹ to Arg in the C-terminal domain of GyrB in E. coli results in MccB17 resistance (263, 266). Several quinolone resistance mutations also result in cross-resistance to MccB17, implying that the binding sites of quinolones and MccB17 may overlap (263), although the location of the mutation at Trp⁷⁵¹ of GyrB implies that the binding sites are distinct. Modification of MccB17 has revealed amino acids in the toxin (Asn⁵³ and Asn⁵⁹) that are required for activity (267). Although the structure of MccB17 is not currently known, a model has been suggested (267), and it is likely that the folded structure is required for biological activity. The novel mode of action of MccB17, distinct from that of quinolone and coumarin drugs, presents scope for the development of small-molecule analogs that could be potential lead molecules for drug design. It is now possible to make MccB17 by chemical synthesis (268, 269), which greatly improves the possibility of making MccB17-based compounds. Some work in this area, utilizing both chemical and genetic methods for making new MccB17s, has been carried out and has revealed the potential of using derivatives of MccB17 as antibacterials (270).

Structure of the DNA gyrase inhibitor MccB17. doi:10.1128/ecosalplus.ESP-0010-2014.f20

Immunity in the MccB17-producing host strains is encoded by the mcbEFG genes (271); one of the gene products is McbG, which is a pentapeptide repeat protein (272). It is interesting that Qnr and MfpA are also in the pentapeptide repeat protein family (260) and that all three are likely to adopt a similar fold and have a similar mode of action, i.e., binding to GyrA as DNA mimics (see below).

Albicidins

Albicidins are antibiotics and phytotoxins produced by the bacterium Xanthomonas albilineans, a plant pathogen responsible for sugarcane leaf scald disease; they have been shown to block prokaryotic DNA replication (273). The target for albicidin is DNA gyrase (274). Albicidin stabilizes the gyrase cleavage complex in an ATP-dependent manner, and cross-resistance is seen with mutations of Ser⁸³ in GyrA that result in quinolone resistance. Albicidin does not inhibit ATPase activity. It has therefore been proposed that albicidin acts in a fashion similar to that of the quinolones but requires the presence of ATP (274). This requirement may be because albicidin binds when the enzyme is in a particular conformation following an ATP-mediated step in the supercoiling cycle. DNA gyrase of X. albilineans is distinct from that of E. coli in terms of its enzymatic properties (for example, showing a high degree of distributive supercoiling and little relaxation activity) and also because the GyrA subunit confers albicidin resistance (275). In addition, X. albilineans encodes a pentapeptide repeat protein, AlbG, within the albicidin biosynthesis region that also confers albicidin resistance (274); this protein is analogous to Qnr of E. coli and MfpA of M. tuberculosis, which confer quinolone resistance (see below). Relatively little is known about the structure of albicidin, aside from the fact that it is thought to contain 38 C atoms and several aromatic rings (276). The heterologous production of albicidin in Xanthomonas axonopodis pv. vesicatoria (277) may present new possibilities for discovering more about this intriguing toxin.

CcdB

CcdB is a ca. 12-kDa protein that is a bacterial toxin, which is coupled with CcdA (a ca. 10-kDa protein) to make up the ccd toxin-antitoxin system (278, 279, 280). Toxin-antitoxin systems are involved in the postsegregational killing of plasmid-cured cells (281). CcdA prevents the action of CcdB by binding tightly to it (282). Cells bearing the F plasmid express both ccdA and ccdB at low levels, but if the F plasmid is lost, CcdA, which is less stable than CcdB, is degraded, leaving no defense against the CcdB toxin (283). CcdB has been shown to target DNA gyrase (279, 282), and the crystal structure of CcdB bound to a section of GyrA has indicated that it acts as a wedge that stabilizes an open conformation of the enzyme with bound DNA (284) (Fig. 21); the data support a model in which CcdB binds to a conformation of gyrase that is revealed during the strand passage reaction (285). Mutation of Arg⁴⁶² to Cys in GyrA confers resistance to CcdB (282); this residue lies in the central cavity of GyrA, consistent with the proposed mechanism of action. Quinolone-resistant gyrase mutants show no cross-resistance to CcdB (286, 287), consistent with their distinct mechanisms of action. The available biochemical evidence suggests that CcdB binds to GyrA during strand passage, when the toxin can gain access to the central cavity (287). Although the action of CcdB was originally thought to be nucleotide dependent (286, 287), later work showed that ATP is not required for CcdB to act on gyrase (285). The antitoxin protein, CcdA, has an intrinsically disordered domain and binds to two partially overlapping binding sites in CcdB to relieve inhibition of gyrase (288).

Its unique mode of action, distinct from that of quinolones and coumarins, makes CcdB an attractive prospect for designing novel gyrase-specific antibacterial agents. However, its large size suggests that this might be challenging; nonetheless, some synthetic fragments have been made (289).

Pentapeptide repeat proteins (Qnr and MfpA)

The pentapeptide repeat proteins are a large family (>500 members) found in prokaryotes and eukaryotes that contain tandemly repeated amino acids (260). Qnr and MfpA were discovered through their ability to protect bacteria from quinolones (see above), but they have subsequently been shown to also be inhibitors of gyrase; QnrA has also been shown to interact with topo IV (290) in addition to gyrase (291). The plasmid-borne gene, qnr, encodes a 218-amino-acid protein (292). The structure of a protein homologous to Qnr, MfpA from M. tuberculosis, has been solved (293); this work reveals a protein fold, the right-handed quadrilateral β-helix, that resembles B-form DNA. This structure derives from the pentapeptide repeat motifs and suggests that other family members also exhibit this structural feature. MfpA was shown to be a DNA mimic capable of inhibiting gyrase activity by competing with DNA for the G-segment-binding site (293). The structures of Qnr homologs from Enterococcus faecalis (294) and Aeromonas hydrophila (295) have also been reported. Although these proteins inhibit gyrase, they also confer protection by preventing cleavage complex formation by other agents. Other relevant pentapeptide proteins are McbG (see above), which is involved in defense against MccB17 (272), and AlbG (see above), which confers albicidin resistance (274); it is likely that these proteins also act by binding to the G-segment-binding site in GyrA.

Other inhibitors

Aside from the drugs and toxins mentioned above, there are other compounds that target bacterial gyrases. about which we know rather less (296). These include cyclothialidines, clerocidin, and GyrI. Cyclothialidines are natural products of Streptomyces species that inhibit gyrase by binding to the ATP-binding site of GyrB in a manner similar to that of aminocoumarins (297). Although these compounds are potent inhibitors of gyrase, they are not very effective as antibacterial agents. Crystal structures of cyclothialidines bound to the N-terminal subdomain of GyrB reveal the details of drug-protein interactions (204, 298). As with aminocoumarins, knowledge of the structure of the drug-protein complex and the availability of pathway engineering in Streptomyces raise the possibility of making more effective analogs of cyclothialidines. However, it has also been shown that this goal can be achieved with synthetic chemistry (299).

Clerocidin is a diterpenoid natural product that can inhibit bacterial gyrase and eukaryotic topo II (300, 301). It is a cleavage complex-stabilizing drug that differs from quinolones in its action. It has also been shown to stabilize cleavage complexes with Streptococcus pneumoniae topo IV (302). Work with S. pneumoniae gyrase has suggested that clerocidin exerts a strong sequence selection for G residues at the gyrase cleavage site and generates a modified guanine at the cleavage site (303).

GyrI is a small (ca. 18-kDa) protein encoded by E. coli that binds to and inhibits DNA gyrase (304, 305); it was also identified independently as SbmC, a protein imparting resistance to MccB17 (306). Like Qnr and MfpA, GyrI can protect DNA from damage from other agents, such as MccB17 and quinolones (307, 308), but it appears to be able to fulfill a broader role, negating the effects of alkylating agents such as mitomycin C and N-methyl-N-nitro-N-nitrosoguanidine (308).

In addition to the above, there are a whole host of other small-molecule inhibitors of gyrase that have appeared in the literature in recent years. Such compounds include naphthoquinones (309), azaindoles (310), pyrrolamides (311), and benzimidazoles (312). The molecular basis of the action of some of these compounds remains to be established. It is not yet clear if any of these compounds will prove to have clinical efficacy to rival that of the fluoroquinolones.

FUTURE DIRECTIONS

DNA topoisomerases have vital roles in DNA metabolism in bacteria and all other organisms. Aside from the need to study these enzymes in order to improve our understanding of cellular processes, their roles as targets for antibacterial agents also necessitate a deeper understanding of these enzymes.

In recent years there have been tremendous strides in the analysis of topoisomerase structure, particularly using X-ray crystallography. This work has provided invaluable insight into topoisomerase mechanisms; it has also revealed the molecular basis of drug action and provided guidance for the development of new agents. However, obtaining structures of complete topoisomerase enzymes has proved challenging, and few are currently available, although there has been recent success with fusion proteins of the subunits of gyrase and topo IV. This will undoubtedly be a goal for future work, revealing new insights into topoisomerase mechanism and presenting new opportunities for drug targeting. In addition, the application of other techniques, such as cryo-EM, small-angle X-ray scattering, and atomic force microscopy, will very likely be important in the further study of topoisomerase structure.

While static structures provide invaluable information, conformational dynamics are key to understanding the action of topoisomerases, as their reactions require large movements in protein and DNA. Although such information can be deduced from X-ray structures, other techniques can be brought to bear here. In particular, there has been recent success with FRET (Förster resonance energy transfer or fluorescence resonance energy transfer) and with single-molecule methods, which are likely to continue to yield useful information. In addition, time-resolved structural techniques, such as time-resolved crystallography and scattering methods, could play a useful part in elucidating the details of conformational changes in topoisomerase reactions.

Although we now understand the basic mechanism of topoisomerase action, important details remain to be revealed, e.g., exactly how the T segment is transferred through the enzymes during the strand passage process, and how the free energy of ATP hydrolysis is transduced into torsional stress in the case of DNA gyrase. The answers to such questions will be useful not only in the topoisomerase field but also to the study of other enzymes that catalyze related reactions, such as those involving recombinases and replication initiation proteins.

Although we can appreciate how topoisomerases function in cells to control DNA topology, for example during DNA replication, other physiological roles of these enzymes are less clear. For example, how topo VI contributes to the process of endoreduplication in plants is presently unclear, and more generally it is not really known how topoisomerases contribute to various recombination processes.

Topoisomerases have been known to be targets for antibacterial agents for about 40 years, but we are still finding new agents that target these enzymes. New compounds that target gyrase/topo IV are continually being found, and it is likely that another class of compounds will be found that will match the fluoroquinolones in terms of their clinical utility. Topo I is not yet a target for clinical antibiotics, but significant effort is under way to establish this enzyme as a future target for new antibacterials.

Figure 17b — **Structure of the N-terminal domain of GyrA (GyrA55) complexed with simocyclinone D8.** The protein dimer is shown in gold and blue (ribbon representation), and the bound simocyclinone D8 dimer is shown in space-filling representation. (A) Side view. (B) Top view. Note that the polyketide end of each simocyclinone molecule also binds to the other monomer across the dimer (DNA-gate) interface (221). doi:10.1128/ecosalplus.ESP-0010-2014.f17b

ACKNOWLEDGMENTS

A.M.’s laboratory is supported by grant BB/J004561/1 from BBSRC and the John Innes Foundation BBSRC; N.G.B. is supported by a studentship from BBSRC and Redx; K.E.-R. was supported by a studentship from BBSRC and Syngenta.

We thank Stephen Hearnshaw for assistance with figures, and Fred Collin and Katarzyna Ignasiak for comments on the manuscript.

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PERMALINK

DNA Topoisomerases

Natassja G Bush

Katherine Evans-Roberts

Anthony Maxwell

Abstract

Figure 1.

Figure 2.

Figure 3.

Figure 4.

CLASSIFICATION OF TOPOISOMERASES

Table 1.

Figure 5.

Figure 6.

Type I Topoisomerases

Topo I

Figure 7.

Figure 8.

Topo III

Topo V

Reverse gyrase

Type II Topoisomerases

Topo II

Figure 9.

Topo VI

Topo IV

Figure 10.

Figure 11.

DNA gyrase

Structure of DNA gyrase

Figure 12.

Mechanism of action of DNA gyrase

Figure 13.

DRUGS AND TOXINS THAT TARGET BACTERIAL DNA TOPOISOMERASES

Topo I

DNA Gyrase

Table 2.

Aminocoumarins

Figure 14.

Figure 15.

Simocyclinones

Figure 16.

Figure 17a.

Quinolones

Figure 18.

Figure 19.

Microcin B17

Figure 20.

Albicidins

CcdB

Figure 21.

Pentapeptide repeat proteins (Qnr and MfpA)

Other inhibitors

FUTURE DIRECTIONS

Figure 17b.

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

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