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Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance.

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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]
Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance.
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  Data: <searchLink fieldCode="AR" term="%22Martins%2C+Ana%22">Martins, Ana</searchLink><br /><searchLink fieldCode="AR" term="%22Judák%2C+Fanni%22">Judák, Fanni</searchLink><br /><searchLink fieldCode="AR" term="%22Farkas%2C+Zoltán%22">Farkas, Zoltán</searchLink><br /><searchLink fieldCode="AR" term="%22Szili%2C+Petra%22">Szili, Petra</searchLink><br /><searchLink fieldCode="AR" term="%22Grézal%2C+Gábor%22">Grézal, Gábor</searchLink><br /><searchLink fieldCode="AR" term="%22Csörgő%2C+Bálint%22">Csörgő, Bálint</searchLink><br /><searchLink fieldCode="AR" term="%22Czikkely%2C+Márton+Simon%22">Czikkely, Márton Simon</searchLink><br /><searchLink fieldCode="AR" term="%22Maharramov%2C+Elvin%22">Maharramov, Elvin</searchLink><br /><searchLink fieldCode="AR" term="%22Daruka%2C+Lejla%22">Daruka, Lejla</searchLink><br /><searchLink fieldCode="AR" term="%22Spohn%2C+Réka%22">Spohn, Réka</searchLink><br /><searchLink fieldCode="AR" term="%22Balogh%2C+Dávid%22">Balogh, Dávid</searchLink><br /><searchLink fieldCode="AR" term="%22Daraba%2C+Andreea%22">Daraba, Andreea</searchLink><br /><searchLink fieldCode="AR" term="%22Juhász%2C+Szilvia%22">Juhász, Szilvia</searchLink><br /><searchLink fieldCode="AR" term="%22Vágvölgyi%2C+Máté%22">Vágvölgyi, Máté</searchLink><br /><searchLink fieldCode="AR" term="%22Hunyadi%2C+Attila%22">Hunyadi, Attila</searchLink><br /><searchLink fieldCode="AR" term="%22Cao%2C+Yihui%22">Cao, Yihui</searchLink><br /><searchLink fieldCode="AR" term="%22Sun%2C+Zhenquan%22">Sun, Zhenquan</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+Xuechen%22">Li, Xuechen</searchLink><br /><searchLink fieldCode="AR" term="%22Papp%2C+Balázs%22">Papp, Balázs</searchLink><br /><searchLink fieldCode="AR" term="%22Pál%2C+Csaba%22">Pál, Csaba</searchLink>
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  Data: Science Translational Medicine; 1/8/2025, Vol. 17 Issue 780, p1-12, 12p
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  Data: <searchLink fieldCode="DE" term="%22GRAM-positive+bacterial+infections%22">GRAM-positive bacterial infections</searchLink><br /><searchLink fieldCode="DE" term="%22MULTIDRUG+resistance%22">MULTIDRUG resistance</searchLink><br /><searchLink fieldCode="DE" term="%22DRUG+resistance+in+bacteria%22">DRUG resistance in bacteria</searchLink><br /><searchLink fieldCode="DE" term="%22BACTERIAL+population%22">BACTERIAL population</searchLink><br /><searchLink fieldCode="DE" term="%22DAPTOMYCIN%22">DAPTOMYCIN</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/scitranslmed.adl2103
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      – Code: eng
        Text: English
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      – SubjectFull: GRAM-positive bacterial infections
        Type: general
      – SubjectFull: MULTIDRUG resistance
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      – SubjectFull: DRUG resistance in bacteria
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      – SubjectFull: DAPTOMYCIN
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              Text: 1/8/2025
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