A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin

Author:

Heo Hee Young1ORCID,Zou Guijin2ORCID,Baek Seongeun1,Kim Jae‐Seok3ORCID,Mylonakis Eleftherios4ORCID,Ausubel Frederick M.56ORCID,Gao Huajian27ORCID,Kim Wooseong1ORCID

Affiliation:

1. College of Pharmacy Graduate School of Pharmaceutical Sciences Ewha Womans University Seoul 03760 Republic of Korea

2. Institute of High Performance Computing (IHPC) Agency for Science Technology and Research (A*STAR) Singapore 138632 Republic of Singapore

3. Department of Laboratory Medicine Kangdong Sacred Heart Hospital Hallym University College of Medicine Seoul 05355 Republic of Korea

4. Department of Medicine Houston Methodist Hospital Houston TX 77030 USA

5. Department of Molecular Biology Massachusetts General Hospital Boston MA 02114 USA

6. Department of Genetics Harvard Medical School Boston MA 02115 USA

7. School of Mechanical and Aerospace Engineering College of Engineering Nanyang Technological University Singapore 639789 Republic of Singapore

Abstract

AbstractInfections caused by Staphylococcus aureus, notably methicillin‐resistant S. aureus (MRSA), pose treatment challenges due to its ability to tolerate antibiotics and develop antibiotic resistance. The former, a mechanism independent of genetic changes, allows bacteria to withstand antibiotics by altering metabolic processes. Here, a potent methylazanediyl bisacetamide derivative, MB6, is described, which selectively targets MRSA membranes over mammalian membranes without observable resistance development. Although MB6 is effective against growing MRSA cells, its antimicrobial activity against MRSA persisters is limited. Nevertheless, MB6 significantly potentiates the bactericidal activity of gentamicin against MRSA persisters by facilitating gentamicin uptake. In addition, MB6 in combination with daptomycin exhibits enhanced anti‐persister activity through mutual reinforcement of their membrane‐disrupting activities. Crucially, the “triple” combination of MB6, gentamicin, and daptomycin exhibits a marked enhancement in the killing of MRSA persisters compared to individual components or any double combinations. These findings underscore the potential of MB6 to function as a potent and selective membrane‐active antimicrobial adjuvant to enhance the efficacy of existing antibiotics against persister cells. The molecular mechanisms of MB6 elucidated in this study provide valuable insights for designing anti‐persister adjuvants and for developing new antimicrobial combination strategies to overcome the current limitations of antibiotic treatments.

Funder

National Research Foundation of Korea

National Institute of Allergy and Infectious Diseases

Korea Basic Science Institute

Ministry of Education - Singapore

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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