Table 2.
Summary of the antibiotics employed and the resistance mechanisms evolved by the ESKAPE pathogens
| Class of antibiotic | Molecular target | Function of the targeted molecule | Organism | Resistance mechanism | Genes involved | References |
|---|---|---|---|---|---|---|
| β-Lactams | Penicillin-binding proteins (PBPs) | Synthesis of peptidoglycan | Enterococcus sp. | Alteration of PBPs | pbp5 | (Beta-Lactam Antibiotics - an overview | ScienceDirect Topics; Miller et al., 2014; Maréchal et al., 2016) |
| Production of β-lactamases | pbp5 | |||||
| Staphylococcus aureus | Alteration of PBPs | pbp2 | (Hackbarth et al., 1995; Foster, 2017) | |||
| Production of β-lactamases | blaZ | |||||
| Klebsiella pneumoniae | Alteration of PBPs | pbp2 and pbp4 | (Lin et al., 2006; Sutaria et al., 2018) | |||
| Production of extended-spectrum β-lactamases (ESBLs) | shv-27 and tem-116 | |||||
| Acinetobacter baumannii | Alteration of PBPs | ponA, mrcB, pbpA, and fts1 | (Cayô et al., 2011; Alkasaby and El Sayed Zaki, 2017; Abdi et al., 2020; Uppalapati et al., 2020) | |||
| Alterations in outer membrane proteins (OMPs) | ompA, carO, and oprD | |||||
| Production of extended-spectrum β-lactamases | tem, shv, and ctx-m | |||||
| High activity of efflux pumps | ade gene cluster | |||||
| Pseudomonas aeruginosa | Alteration of PBPs | pbp2 and pbp3 | (Pechère and Köhler, 1999; Giske et al., 2008; Poole, 2011) | |||
| Alterations in permeability | oprD | |||||
| Production of β-lactamases | ampC and poxB | |||||
| High activity of efflux pumps | mexAB-oprM, mexCD-oprJ, and mexXY-oprM | |||||
| Enterobacter sp. | Alteration of PBPs | pbp3 | (Chen et al., 2017; Wu et al., 2018) | |||
| Production of β-lactamases | bla-shv12 and bla-mir | |||||
| Aminoglycosides | Ribosome | Bacterial protein synthesis | Enterococcus sp. | Aminoglycoside-modifying enzyme | aph(2″)-Ib, aph(2″)-Ic, and aph(2″)-Id | (Chow, 2000) |
| S. aureus | Aminoglycoside-modifying enzymes (AMEs) |
aac(6′)-Ie +aph(2″, ant(4’)Ia, aph(3′)IIIa, and ant(6)-Ia |
(Rahimi, 2016) | |||
| K. pneumoniae | Aminoglycoside-modifying enzymes (AMEs) | aac(3)ii, aac (6′)-ib, ant (3″)-i, and ant (2″)-i | (Liang et al., 2015) | |||
| A. baumannii | Aminoglycoside-modifying enzymes (AMEs) | aac(3)-i, aph(3′)-vi, and ant(3″)-i | (Tahbaz et al., 2019) | |||
| P. aeruginosa | Aminoglycoside-modifying enzymes (AMEs) | aac(6′)-Ib, aphA1, and aadB | (Teixeira et al., 2016) | |||
| Enterobacter sp. | Ribosomal modification | rmtE | (Garneau-Tsodikova and Labby, 2016) | |||
| Chloramphenicol* | 50S ribosomal subunit | Peptidyl transferase activity | Enterococcus sp. | Inactivation of chloramphenicol | catA7, catA8, and catA9 | (Hasani et al., 2012) |
| S. aureus | Inactivation of chloramphenicol | cat genes | (Genetics of Antimicrobial Resistance in Staphylococcus Aureus) | |||
| K. pneumoniae | Inactivation of chloramphenicol | catB3, catA1, and catA2 | (Mbelle et al., 2020) | |||
| A. baumannii | Inactivation of chloramphenicol by the action of chloramphenicol acyltransferase | ABUW_0982 of CHL gene cluster | (Karalewitz and Millera, 2018) | |||
| P. aeruginosa | Inactivation of chloramphenicol | catB7 | (White et al., 1999) | |||
| Enterobacter sp. | Efflux pumps | AcrAB–TolC and eefABC | (Davin-Regli and Pagès, 2015) | |||
| Glycopeptides | Peptidoglycan precursors | Synthesis of peptidoglycan, by preventing transglycosylation and transpeptidation | Enterococcus sp. | Change in the amino acid sequence of the precursor of peptidoglycan | vanH, vanA, and vanZ | (Miller et al., 2014) |
| S. aureus | Modification of the target molecule | pbp2 | (Foster, 2017; Yushchuk et al., 2020) | |||
| Modification of the target | vanA | |||||
| K. pneumoniae | – | - | – | |||
| A. baumannii | – | - | – | |||
| P. aeruginosa | Adhesin factor*// | lecA | (Pang et al., 2019) | |||
| Enterobacter sp. | – | - | – | |||
| Tetracyclines* | 30S ribosomal subunit | Bacterial protein synthesis | Enterococcus sp. | Efflux pumps | tetM and tetL | |
| S. aureus | Efflux pumps | tetA(K) and tetA(L) | (Foster, 2017) | |||
| K. pneumoniae | Efflux pumps | tetA and tetB | (Bokaeian et al., 2014) | |||
| A. baumannii | Efflux pumps | tetA and tetB | (Maleki et al., 2014) | |||
| P. aeruginosa | Efflux pumps | tetR, lysR, marR, and araC | (Issa et al., 2018) | |||
| Enterobacter sp. | Efflux pumps | AcrAB–TolC and eefABC | (Davin-Regli and Pagès, 2015) | |||
| Oxazolidinones* | Ribosome | Bacterial protein synthesis | Enterococcus sp. | Alterations in oxazolidinone binding sites | G2576T mutation in the V domain of the 23S rRNA gene | (Chen et al., 2019) |
| S. aureus | Alterations in oxazolidinone binding sites | U2500A and G2447U mutations in the 23S rRNA encoding gene | (Long and Vester, 2012) | |||
| K. pneumoniae | PhoPQ‐governed lipid A remodeling | mgrB mutation | (Kidd et al., 2017) | |||
| A. baumannii | Modification of target | Mutations in the 23S rRNA encoding gene | (Vrancianu et al., 2020a) | |||
| P. aeruginosa | – | - | – | |||
| Enterobacter sp. | Modification of target | G2576T mutations | (Deshpande et al., 2018) | |||
| Mobile Genetic Elements | optrA | |||||
| Macrolides* | Ribosome | Bacterial protein synthesis | Enterococcus sp. | – | – | – |
| Staphylococcu S. aureus |
Modification of target | erm(B) | (Schmitz et al., 2000; Wolter et al., 2005; Taitt et al., 2014) | |||
| Efflux pumps | mef(A), msrA, and msrB | |||||
| Modification of binding site | Mutations in 23S rRNA and riboproteins L4 and L22 | |||||
| K. pneumoniae | – | – | – | |||
| A. baumannii | Efflux pump | adeRS | (Vrancianu et al., 2020a) | |||
| P. aeruginosa | Efflux pump | Mutation in MexCD-OprJ | (Pang et al., 2019) | |||
| Enterobacter sp. | – | – | – | |||
| Ansamycins | RNA polymerase | Transcription | Enterococcus sp. | Modification of target | Substitution in rpoB gene | (Enne et al., 2004) |
| S. aureus | Modification of target | Mutation in rpoB gene | (Wang C. et al., 2019) | |||
| K. pneumoniae | Modification of target *// | arr2 | (Tribuddharat and Fennewald, 1999; Arlet et al., 2001) | |||
| A. baumannii | Modification of target | Mutation in rpoB gene | (Giannouli et al., 2012) | |||
| P. aeruginosa | Modification of target | Mutation in rpoB gene | (Yee et al., 1996) | |||
| Enterobacter sp. | Alteration of binding sites | Mutation in Rifampin resistance-determining region (RRDR) | (Weinstein and Zaman, 2019) | |||
| Modification of target | Substitution in rpoB gene | |||||
| Streptogramins | 23S rRNA of 50S ribosomal subunit | Bacterial protein synthesis | Enterococcus sp. | Alteration of binding sites | erm | (Hershberger et al., 2004) |
| S. aureus | Alteration of binding sites | ermA and ermC | (Lina et al., 1999) | |||
| K. pneumoniae | rRNA modification | erm | (Ogawara, 2019) | |||
| A. baumannii | – | - | – | |||
| P. aeruginosa | – | - | – | |||
| Enterobacter sp. | Efflux pump | Lsa | (Poole, 2007) | |||
| Lipopeptides | Multiple targets | Multiple functions | Enterococcus sp. | Modification of cell envelope stress response | LiaR | (Arias et al., 2011; Tran et al., 2013; Reyes et al., 2015) |
| Modification of membrane phospholipid mechanism | Cls and GdpD | |||||
| S. aureus | Mutations in RNA polymerase | rpoC and rpoB | (Montera et al., 2008) | |||
| Mutation in lysylphosphatid-ylglycerol synthetase | mprF | |||||
| Mutation in histidine kinase | yycG | |||||
| K. pneumoniae | – | - | – | |||
| A. baumannii | Persister formation | Mutation in ΔrelA | (Monem et al., 2020) | |||
| P. aeruginosa | – | - | – | |||
| Enterobacter sp. | – | - | – |
In some cases, resistance is caused when combinatorial therapy is employed. In fact, it is reported that certain combinations of antibiotics could induce resistance (Liu et al., 2020). Therefore, it is important to choose the right combination of antibiotics.
*Bacteriostatic activity.
"-" denotes insufficient information.