TABLE 3.
Inhibitors discovered through enzyme screening or designd
| Target | Function | Nonantibacterial enzyme inhibitor(s) | Antibacterial inhibitor(s) (some with SAR) | Inhibitor(s) with some genetic/phenotypic evidence (but insufficient for proof) | Inhibitor(s) with probable additional target | Well-validated antibacterial inhibitor(s) |
|---|---|---|---|---|---|---|
| MurA | Cell wall | T6362R (107) | Compound 1 (28) | |||
| Three compounds (33) | ||||||
| MurI | Glu racemase | d-Glu analogsb (88) | Pyrazolopyrimidinedione (89) | |||
| Cell wall | Pyridodiazepine amines (129) | |||||
| MurG | Cell wall | Rhodanines (163) | ||||
| WalK/WalR | Cell wall regulation | Thiazolidinones,c benzamides,c pyrimidinonec (305) | ||||
| UppS | Bactoprenol synthesis | Tetramicc and tetronicc acids (297) | ||||
| FtsZ | Cell division | Zantrins (236) | ||||
| C-seco-taxanesb (164) | 3-Methoxybenzamide (MBO) (277) | |||||
| Dichamanetin (372) | PC190723b (81, 151) | |||||
| Viridotoxin (379) | Cmpd 2 (MBO derivative)b (150) | |||||
| 4-Aminofurazan (173) | ||||||
| FabI (FabL and -K) | Fatty acid synthesis | Luteolinc (396) | Imidazoles (154) | Thiopyridines (214) | Aminopyridines (177, 258, 294) | |
| Enoyl-reductases | Aquastatins (203) | AFN1252a (185), MUT37307a,b(106), CG400549 (290) | ||||
| Curcuminc (396) | ||||||
| FabK | Fatty acid synthesis | Phenylimidazole derivatives of 4-pyridoneb (193), AG205 (357) | ||||
| Enoyl-reductases | ||||||
| CoaA | Coenzyme A | Pantothenic acid derivativesb (74) | ||||
| AccA, AccD | Acetyl-CoA carboxylase | Moiramide B (120, 121) | ||||
| Pyridopyrimidines (255) | ||||||
| Pyrrolidinediones (122) | ||||||
| LpxC | Lipid A deacetylase | UDP analogsc (25) | BB-78485 (76) | |||
| Hydantoinsb (80) | CHIR-090b (247) | |||||
| LptD (Imp) | LPS translocase | Peptidomimetic (350) | ||||
| RpoB and -C | RNA polymerase | SB-2 (rhodanine) (10) | CBR703 (15) | |||
| Ureidothiphenes (14) | ||||||
| Ef-Tu | Translation elongation | Indole-dipeptide (176) | ||||
| LeuRS | Leu tRNA synthetase | ABX (benzoxaborole) (123) | ||||
| MetRS | Met tRNA synthetase | REP 8839 (139, 175) | ||||
| PheRS | Phe tRNA synthetase | Thiazolylurea-sulfonamides (38) | ||||
| Spirocyclic tetrahydrofurans (157) | ||||||
| Peptidyl deformylase | Actinonin (68), BB-3497a (75) | |||||
| Ro 66-6976, Ro 66-0376 (66) | ||||||
| LBM-415a (209), N-alkyl urea hydroxamic acids (145) | ||||||
| Map | Met aminopeptidase | Pyrazolediaminesc (109) | Catechol thiazoles, catechol thiophenes (382) | |||
| PolC | DNA polymerase IIIC | Anilinopyrazolopyrimidinonesb (4) | Anilino-uracilsb (53, 221) | |||
| HB-EMAUb (59), EMAIPUb (199) | ||||||
| DnaG | DNA primase | Benzopyrimido-furans,c pyridothieno-pyrimidinec | ||||
| MenA | Menaquinone synthase | Hydrazine or tertiary or secondary amine-containing mimics of demethylmenaquinoneb (200) | ||||
| ClpXP | Protease | Cyclic peptide IXP1 (70) | ||||
| DnaK | Chaperone | Tetradecanoyl-aminomethylbenzoyl- l-isoleucineb (213) | ||||
| His kinases | Signal transducers | Thieno-pyridine (132) |
a
Compound has reached clinical trials.
b
Compound or series based on substrates or optimized from previously known inhibitors.
c
Compound or series discovered through in silico screening based on crystallographic data.
d
Definitions of column headings are given in the text.