Podoll Jessica, Olson Justin, Wang Wei, Wang Xiang
Department of Chemistry, University of Colorado, Boulder, CO 80309, USA.
Antibiotics (Basel). 2021 Mar 18;10(3):315. doi: 10.3390/antibiotics10030315.
Antibacterial discovery efforts have lagged far behind the need for new antibiotics. An approach that has gained popularity recently is targeting bacterial phospholipid membranes. We leveraged the differences between bacterial and mammalian phospholipid compositions to develop a high-throughput screen that identifies agents that selectively disrupt bacterial membranes while leaving mammalian membranes intact. This approach was used to screen 4480 compounds representing a subset of the Maybridge HitFinder V.11 Collection and the Prestwick Chemical Drug Library. The screen identified 35 "positives" (0.8% hit rate) that preferentially damage bacterial model membranes. Among these, an antimalarial compound, mefloquine, and an aminoglycoside, neomycin, were identified. Further investigation of mefloquine's activity against showed that it has little antibiotic activity on its own but can alter membrane fluidity, thereby potentiating a β-lactam antibiotic, oxacillin, against both methicillin-susceptible and methicillin-resistant . This study indicates that our cell-free screening approach is a promising platform for discovering bacterial membrane disruptors as antibacterials antibiotic adjuvants.
抗菌药物的研发工作远远落后于对抗新抗生素的需求。最近一种流行的方法是针对细菌磷脂膜。我们利用细菌和哺乳动物磷脂成分的差异，开发了一种高通量筛选方法，以识别能够选择性破坏细菌膜同时保持哺乳动物膜完整的药物。该方法用于筛选代表Maybridge HitFinder V.11文库和Prestwick化学药物库子集的4480种化合物。筛选出35种“阳性”化合物（命中率为0.8%），它们优先损害细菌模型膜。其中，鉴定出一种抗疟化合物甲氟喹和一种氨基糖苷类药物新霉素。对甲氟喹活性的进一步研究表明，它自身几乎没有抗生素活性，但可以改变膜流动性，从而增强β-内酰胺类抗生素苯唑西林对甲氧西林敏感菌和耐甲氧西林菌的抗菌作用。这项研究表明，我们的无细胞筛选方法是发现细菌膜破坏剂作为抗菌抗生素佐剂的一个有前景的平台。
