허희영 (이화여자대학교)

한빛사논문

조회356

허희영Hee Young Heo

이화여자대학교

Adv. Sci., Dec 21 2023, | https://doi.org/10.1002/advs.202306112 A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin

Hee Young Heo ¹, Guijin Zou ², Seongeun Baek ¹, Jae-Seok Kim ³, Eleftherios Mylonakis ⁴, Frederick M Ausubel ^5,6, Huajian Gao^2,7, Wooseong Kim ¹

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

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

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

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

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

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

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

CORRESPONDING AUTHOR : Wooseong Kim

Abstract

Infections 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.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2023-12-22)
연구진국내(교신)+국외 연구진
분야 의약학 > 약학

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