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FabI Inhibitor Design
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| The increasing prevalence of antibiotic resistance of certain
bacteria is well–documented. To develop new antibiotics we are
targeting of the fatty acid biosynthesis pathway, as this pathways is
essential for bacterial growth and it represents validated targets for
antibiotic development for several reasons. Fatty acids are
synthesized by mammals (FAS I) and bacteria (FAS II) via substantially
different biosynthetic mechanisms, thus providing the possibility of
bacteria–specific drug targeting. FAS I involves a single
multifunctional enzyme–acyl carrier protein (ACP) complex, whereas FAS
II utilizes several small monofunctional enzymes that operate in
conjunction with ACP–associated substrates. Recent studies have
revealed that the genes responsible for FAS II are essential in
Bacillus subtilis, a close relative of B. anthracis. Enoyl–ACP reductase or FabI, the product of the fabI gene, is an NADH–dependent, key enzyme in the FAS II path that catalyzes the final and rate–determining step of chain elongation. Considerable research over the past few years has shown that enoyl–ACP reductase in a number of pathogens is efficiently inhibited by antibacterial agents including isoniazid, diazaboranes, triclosan, and several other small molecule inhibitors. API-1252, a recently developed FabI inhibitor shows excellent in vitro activity against clinical isolates of Staphylococcus epidermidis and Staphylococcus aureus. Another novel FabI inhibitor, CG400462, was recently reported to show efficacy against Staphylococcus aureus infected mice. These studies clearly indicate that inhibition of enoyl–ACP reductase is a viable approach to develop new antibacterials with novel modes of action. |
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Recent papers from
our lab on FabI inhibitor development:
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