title: AFN-1252 is a potent inhibitor of enoyl-ACP reductase from Burkholderia pseudomallei--Crystal structure, mode of action, and biological activity.
abstract: Melioidosis is a tropical bacterial infection caused by Burkholderia pseudomallei (B. pseudomallei; Bpm), a Gram-negative bacterium. Current therapeutic options are largely limited to trimethoprim-sulfamethoxazole and β-lactam drugs, and the treatment duration is about 4 months. Moreover, resistance has been reported to these drugs. Hence, there is a pressing need to develop new antibiotics for Melioidosis. Inhibition of enoyl-ACP reducatase (FabI), a key enzyme in the fatty acid biosynthesis pathway has shown significant promise for antibacterial drug development. FabI has been identified as the major enoyl-ACP reductase present in B. pseudomallei. In this study, we evaluated AFN-1252, a Staphylococcus aureus FabI inhibitor currently in clinical development, for its potential to bind to BpmFabI enzyme and inhibit B. pseudomallei bacterial growth. AFN-1252 stabilized BpmFabI and inhibited the enzyme activity with an IC50 of 9.6 nM. It showed good antibacterial activity against B. pseudomallei R15 strain, isolated from a melioidosis patient (MIC of 2.35 mg/L). X-ray structure of BpmFabI with AFN-1252 was determined at a resolution of 2.3 Å. Complex of BpmFabI with AFN-1252 formed a symmetrical tetrameric structure with one molecule of AFN-1252 bound to each monomeric subunit. The kinetic and thermal melting studies supported the finding that AFN-1252 can bind to BpmFabI independent of cofactor. The structural and mechanistic insights from these studies might help the rational design and development of new FabI inhibitors.
authors: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial area, Electronic city Phase II, Hosur Road, Bangalore, 560 100, India.
authors: Krishnamurthy Narasimha
authors: KN
authors: Rao
authors: Anirudha
authors: A
authors: Lakshminarasimhan
authors: Sarah
authors: S
authors: Joseph
authors: Swathi U
authors: SU
authors: Lekshmi
authors: Ming-Seong
authors: MS
authors: Lau
authors: Mohammed
authors: M
authors: Takhi
authors: Kandepu
authors: K
authors: Sreenivas
authors: Sheila
authors: S
authors: Nathan
authors: Rohana
authors: R
authors: Yusof
authors: Noorsaadah
authors: N
authors: Abd Rahman
authors: Murali
authors: M
authors: Ramachandra
authors: Thomas
authors: T
authors: Antony
authors: Hosahalli
authors: H
authors: Subramanya
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use; D001572:Benzofurans / Q000737:chemistry* / Q000627:therapeutic use; D016957:Burkholderia pseudomallei / Q000187:drug effects / Q000201:enzymology*; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008554:Melioidosis / Q000188:drug therapy / Q000201:enzymology* / Q000382:microbiology; D011753:Pyrones / Q000737:chemistry* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology
chemical_list: C521531:API 1252; D000900:Anti-Bacterial Agents; D001572:Benzofurans; D011753:Pyrones; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: AFN-1252; Burkholderia pseudomallei; FabI; Melioidosis
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