Maharramov Elvin, Czikkely Márton Simon, Szili Petra, Farkas Zoltán, Grézal Gábor, Daruka Lejla, Kurkó Eszter, Mészáros Léna, Daraba Andreea, Kovács Terézia, Bognár Bence, Juhász Szilvia, Papp Balázs, Lázár Viktória, Pál Csaba
Synthetic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research Centre Szeged, Szeged, Hungary.
Doctoral School of Biology, University of Szeged, Szeged, Hungary.
Nat Commun. 2025 Feb 21;16(1):1842. doi: 10.1038/s41467-025-56934-3.
Antibiotics that target multiple cellular functions are anticipated to be less prone to bacterial resistance. Here we hypothesize that while dual targeting is crucial, it is not sufficient in preventing resistance. Only those antibiotics that simultaneously target membrane integrity and block another cellular pathway display reduced resistance development. To test the hypothesis, we focus on three antibiotic candidates, POL7306, Tridecaptin M152-P3 and SCH79797, all of which fulfill the above criteria. Here we show that resistance evolution against these antibiotics is limited in ESKAPE pathogens, including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, while dual-target topoisomerase antibiotics are prone to resistance. We discover several mechanisms restricting resistance. First, de novo mutations result in only a limited elevation in resistance, including those affecting the molecular targets and efflux pumps. Second, resistance is inaccessible through gene amplification. Third, functional metagenomics reveal that mobile resistance genes are rare in human gut, soil and clinical microbiomes. Finally, we detect rapid eradication of bacterial populations upon toxic exposure to membrane targeting antibiotics. We conclude that resistance mechanisms commonly found in natural bacterial pathogens provide only limited protection to these antibiotics. Our work provides guidelines for the future development of antibiotics.
靶向多种细胞功能的抗生素预计不易产生细菌耐药性。在此，我们假设虽然双重靶向至关重要，但在预防耐药性方面并不充分。只有那些同时靶向膜完整性并阻断另一条细胞途径的抗生素，其耐药性发展才会降低。为了验证这一假设，我们聚焦于三种候选抗生素，POL7306、Tridecaptin M152 - P3和SCH79797，它们均符合上述标准。在此我们表明，在包括大肠杆菌、肺炎克雷伯菌、鲍曼不动杆菌和铜绿假单胞菌在内的ESKAPE病原体中，针对这些抗生素的耐药性进化是有限的，而双重靶向拓扑异构酶的抗生素则易于产生耐药性。我们发现了几种限制耐药性的机制。首先，从头突变导致的耐药性升高有限，包括那些影响分子靶点和外排泵的突变。其次，通过基因扩增无法产生耐药性。第三，功能宏基因组学表明，移动耐药基因在人类肠道、土壤和临床微生物群落中很少见。最后，我们检测到在暴露于靶向膜的抗生素产生毒性时，细菌群体被迅速根除。我们得出结论，天然细菌病原体中常见的耐药机制对这些抗生素仅提供有限的保护。我们的工作为抗生素的未来开发提供了指导方针。
