Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
Laboratory of Gene Technology, KU Leuven, Kasteelpark Arenberg 21, PO Box 2462, 3001, Heverlee, Belgium.
Angew Chem Int Ed Engl. 2020 Jun 22;59(26):10549-10556. doi: 10.1002/anie.201915407. Epub 2020 Apr 14.
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.
烯酰基辅酶 A 还原酶 FabI 是金黄色葡萄球菌脂肪酸生物合成所必需的酶，是开发新型、急需的抗葡萄球菌药物的有希望的靶标。在这里，我们阐明了卡里曼他汀类抗生素的作用模式，这是一类新型的 FabI 抑制剂，对多药耐药性金黄色葡萄球菌具有临床相关的活性。通过将 X 射线晶体学与分子动力学模拟、体外动力学研究和化学衍生化实验相结合，我们描述了抗生素与其靶标的相互作用，并证明了卡里曼他汀类以一种独特的构象结合，与其他已知的 FabI 抑制剂的结合模式有很大的不同。我们还研究了金黄色葡萄球菌获得性耐药的机制，并确定了 FabI 中的关键残基，这些残基稳定了抗生素的结合。我们的研究结果为一类新型 FabI 抑制剂的作用模式提供了有趣的见解，这将为未来的抗葡萄球菌药物开发提供灵感。
