Exploring the principles behind antibiotics with limited resistance

Elvin Maharramov, Márton Simon Czikkely, Petra Szili, Zoltán Farkas, Gábor Grézal, Lejla Daruka, Eszter Kurkó, Léna Mészáros, Andreea Daraba, Terézia Kovács, Bence Bognár, Szilvia Juhász, Balázs Papp, Viktória Lázár and Csaba Pál ()
Additional contact information
Elvin Maharramov: HUN-REN Biological Research Centre Szeged
Márton Simon Czikkely: HUN-REN Biological Research Centre Szeged
Petra Szili: HUN-REN Biological Research Centre Szeged
Zoltán Farkas: HUN-REN Biological Research Centre Szeged
Gábor Grézal: HUN-REN Biological Research Centre Szeged
Lejla Daruka: HUN-REN Biological Research Centre Szeged
Eszter Kurkó: HUN-REN Biological Research Centre Szeged
Léna Mészáros: Budapesti út 9
Andreea Daraba: HUN-REN Biological Research Centre Szeged
Terézia Kovács: HUN-REN Biological Research Centre Szeged
Bence Bognár: HUN-REN Biological Research Centre Szeged
Szilvia Juhász: HUN-REN Biological Research Centre Szeged
Balázs Papp: HUN-REN Biological Research Centre Szeged
Viktória Lázár: HUN-REN Biological Research Centre Szeged
Csaba Pál: HUN-REN Biological Research Centre Szeged

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56934-3

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