Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance

Martins, Ana and Judák, Fanni Orsolya and Farkas, Zoltán and Szili, Petra and Grézal, Gábor and Csörgő, Bálint and Czikkely, Márton Simon and Maharramov, Elvin and Daruka, Lejla and Spohn, Réka and Balogh, Dávid and Daraba, Andreea and Juhász, Szilvia and Vágvölgyi, Máté and Hunyadi, Attila and Cao, Yihui and Sun, Zhenquan and Li, Xuechen and Papp, Balázs and Pál, Csaba (2025) Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance. SCIENCE TRANSLATIONAL MEDICINE, 17 (780). No.-eadl2103. ISSN 1946-6234

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Abstract

Several antibiotic candidates are in development against Gram-positive bacterial pathogens, but their long-term utility is unclear. To investigate this issue, we studied the laboratory evolution of resistance to antibiotics that have not yet reached the market. We found that, with the exception of compound SCH79797, antibiotic resistance generally readily evolves in Staphylococcus aureus . Cross-resistance was detected between such candidates and antibiotics currently in clinical use, including vancomycin, daptomycin, and the promising antibiotic candidate teixobactin. These patterns were driven by overlapping molecular mechanisms through mutations in regulatory systems. In particular, teixobactin-resistant bacteria displayed clinically relevant multidrug resistance and retained their virulence in an invertebrate infection model, raising concerns. More generally, we demonstrate that putative resistance mutations against candidate antibiotics are already present in natural bacterial populations. Therefore, antibiotic resistance in nature may evolve readily from the selection of preexisting genetic variants. Our work highlights the importance of predicting future evolution of resistance to antibiotic candidates at an early stage of drug development.

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