期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 26, 页码 10549-10556出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201915407
关键词
antibiotics; inhibitors; MRSA; natural products; protein structures
资金
- European Commission [656067]
- Research Foundation Flanders
- EPSRC [1943244] Funding Source: UKRI
- Marie Curie Actions (MSCA) [656067] Funding Source: Marie Curie Actions (MSCA)
The enoyl-acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti-staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically-relevant activity against multidrug-resistant S. aureus. By combining X-ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti-staphylococcal drug development.
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