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ORIGINAL RESEARCH article

Front. Cell. Infect. Microbiol.
Sec. Antibiotic Resistance and New Antimicrobial drugs
Volume 14 - 2024 | doi: 10.3389/fcimb.2024.1453233
This article is part of the Research Topic Emerging Leaders in Antibiotic Resistance: Pioneering Research and Future Directions View all 6 articles

Phenotypic and genetic characterization of daptomycin nonsusceptible Staphylococcus aureus strains selected by adaptive laboratory evolution

Provisionally accepted
Fangyou Yu Fangyou Yu *Yanlei Xu Yanlei Xu Yanghua Xiao Yanghua Xiao Huilin Zhao Huilin Zhao Bingjie Wang Bingjie Wang Jingyi Yu Jingyi Yu Yongpeng Shang Yongpeng Shang Ying Zhou Ying Zhou Xiaocui Wu Xiaocui Wu Yinjuan Guo Yinjuan Guo *
  • Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

The final, formatted version of the article will be published soon.

    Background: Daptomycin non-susceptible Staphylococcus aureus (DNS) strains pose a serious clinical threat, but their characterization remains limited. Methods: DNS derivatives were generated by exposing S. aureus strains to subinhibitory concentrations of daptomycin. Competition experiments and growth kinetics experiment were used to observe the growth of bacteria. Galleria mellonella larvae and mouse skin abscess models were used to observe the virulence of bacterial. Transmission electron microscopy (TEM), cytochrome C experiments and biofilm formation experiments were used to observe the drug resistance phenotype. And homologous recombination was used to study the role of mutations. Results: Phenotypic profiling of DNS strains revealed impaired growth, increased cell wall thickness, enhanced biofilm formation, reduced negative surface charge, and attenuated virulence compared to their wild-type strains. Whole genome sequencing identified mutations in mprF, cls2, and saeR in DNS strains. Allelic replacement experiments validated the roles of MprF L341F and Cls2 F60S substitutions in augmenting daptomycin non-susceptibility in Newman. Deletion of saeR in the NewmanMprFL341F strain and complementation of saeR in the Newman-DNS strain did not directly alter daptomycin susceptibility. However, the deletion of saeR was found to enhance competitive fitness under daptomycin pressure. Conclusion: This work validates adaptive laboratory evolution (ALE) for modeling clinical DNS strains and uncovers contributions of mprF, cls2, and saeR mutations to the adaptation and resistance mechanisms of S. aureus against daptomycin. These findings enrich our understanding of how S. aureus acquired resistance to daptomycin, thus paving the way for the development of more effective treatment strategies and offering potential molecular markers for resistance surveillance.

    Keywords: Staphylococcus aureus, Daptomycin, Non-susceptible, MPRF, SaeR

    Received: 22 Jun 2024; Accepted: 30 Sep 2024.

    Copyright: © 2024 Yu, Xu, Xiao, Zhao, Wang, Yu, Shang, Zhou, Wu and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Fangyou Yu, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
    Yinjuan Guo, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

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