| Title: |
Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance. |
| Authors: |
Martins, Ana, Judák, Fanni, Farkas, Zoltán, Szili, Petra, Grézal, Gábor, Csörgő, Bálint, Czikkely, Márton Simon, Maharramov, Elvin, Daruka, Lejla, Spohn, Réka, Balogh, Dávid, Daraba, Andreea, Juhász, Szilvia, Vágvölgyi, Máté, Hunyadi, Attila, Cao, Yihui, Sun, Zhenquan, Li, Xuechen, Papp, Balázs, Pál, Csaba |
| Source: |
Science Translational Medicine; 1/8/2025, Vol. 17 Issue 780, p1-12, 12p |
| Subject Terms: |
GRAM-positive bacterial infections, MULTIDRUG resistance, DRUG resistance in bacteria, BACTERIAL population, DAPTOMYCIN |
| 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. Editor's summary: Antibiotic development requires a great deal of research and funding, only for many candidate antibiotics to be beset by the onset of pathogen resistance once reaching the clinic. Martins et al. found that multiple antibiotics, either currently in development or recently clinically approved, readily elicited resistance in Staphylococcus aureus under lab conditions. This resistance evolved from mutations already present in natural bacterial populations. The authors also found evidence of cross-resistance between some antibiotics, in some cases unidirectional, and performed an analysis of whether coresistance might have arisen because of shared targets. These findings highlight the importance of examining the propensity of pathogens to evolve resistance to antibiotic candidates and provide a systematic pathway for its assessment. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
