Clarke Justin E, Galarion Luiza H, Almadani Abdulmenem A, Smith Christopher N A, Wright John D, Warriner Stuart L, O'Neill Alex J
Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
mBio. 2025 Aug 13;16(8):e0161625. doi: 10.1128/mbio.01616-25. Epub 2025 Jul 9.
Among the most significant challenges in antibacterial discovery is achieving delivery of small molecule inhibitors across the bacterial membrane(s) to reach their intracellular targets. It is considered axiomatic that the typical route for antibiotics across the cytoplasmic membrane (CM) involves diffusion directly through the lipid bilayer, though this concept has not translated into actionable information for rationally achieving ingress of inhibitors into bacteria. Here, using antibiotic accumulation measurements in bacteria inactivated for individual or multiple CM transporters, we provide evidence that a diverse range of established antibiotic classes are transported across the CM by hitch-hiking on carrier proteins. The chemical similarity between some antibiotic classes and the native substrate(s) of the importer they share provides a molecular logic for drug transport. Our results indicate that carrier-mediated uptake is a common route of antibiotic entry into bacteria and highlight the value of metabolite mimicry in designing new antibacterial drugs.
Increasing antibiotic resistance among pathogenic bacteria is undermining our ability to treat infection, and new antibacterial drugs are urgently needed to address the problem. One of the most significant challenges in antibacterial discovery is achieving delivery of inhibitors across the bacterial membrane(s) to reach their intracellular targets, reflecting the lack of a granular understanding about how antibiotics enter bacteria. Here, we provide evidence that a common route for established antibiotics into bacteria involves uptake by membrane transport proteins. Our findings thereby offer a clear route forward for antibacterial discovery: mimicry of the natural substrates of transporter proteins to achieve carrier-mediated uptake of inhibitors into the bacterial cell.
在抗菌药物研发中，最重大的挑战之一是如何将小分子抑制剂运送穿过细菌细胞膜，以抵达其细胞内靶点。人们普遍认为，抗生素穿过细胞质膜（CM）的典型途径是直接通过脂质双层进行扩散，不过这一概念尚未转化为可用于合理实现抑制剂进入细菌的可行信息。在此，我们通过对单个或多个CM转运蛋白失活的细菌进行抗生素积累测量，提供证据表明，多种已确立的抗生素类别是通过搭乘载体蛋白的方式穿过CM的。某些抗生素类别与其所共享的转运蛋白的天然底物之间的化学相似性为药物转运提供了分子逻辑。我们的结果表明，载体介导的摄取是抗生素进入细菌的常见途径，并突出了代谢物模拟在设计新型抗菌药物中的价值。
致病细菌中抗生素耐药性的不断增加正在削弱我们治疗感染的能力，因此迫切需要新的抗菌药物来解决这一问题。抗菌药物研发中最重大的挑战之一是如何将抑制剂运送穿过细菌细胞膜，以抵达其细胞内靶点，这反映出我们对抗生素如何进入细菌缺乏深入的了解。在此，我们提供证据表明，已确立的抗生素进入细菌的常见途径是通过膜转运蛋白进行摄取。因此，我们的研究结果为抗菌药物研发提供了一条明确的前进道路：模拟转运蛋白的天然底物，以实现载体介导的抑制剂进入细菌细胞。
