Unknown

Dataset Information

0

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 ?-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.

SUBMITTER: Rao KN 

PROVIDER: S-EPMC4420531 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

AFN-1252 is a potent inhibitor of enoyl-ACP reductase from Burkholderia pseudomallei--Crystal structure, mode of action, and biological activity.

Rao Krishnamurthy Narasimha KN   Lakshminarasimhan Anirudha A   Joseph Sarah S   Lekshmi Swathi U SU   Lau Ming-Seong MS   Takhi Mohammed M   Sreenivas Kandepu K   Nathan Sheila S   Yusof Rohana R   Abd Rahman Noorsaadah N   Ramachandra Murali M   Antony Thomas T   Subramanya Hosahalli H  

Protein science : a publication of the Protein Society 20150402 5


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 pa  ...[more]

Similar Datasets

| S-EPMC5401771 | biostudies-literature
| S-EPMC3632907 | biostudies-literature
| S-EPMC3868742 | biostudies-literature
| S-EPMC3486558 | biostudies-literature
| S-EPMC4278936 | biostudies-literature
| S-EPMC5947681 | biostudies-literature
| S-EPMC3519566 | biostudies-literature
| S-EPMC3527710 | biostudies-literature
2010-07-02 | GSE19400 | GEO
| S-EPMC5676022 | biostudies-literature