A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin
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 antibiotic...
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| Format: | Article |
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Wiley
2024-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202306112 |
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| author | Hee Young Heo Guijin Zou Seongeun Baek Jae‐Seok Kim Eleftherios Mylonakis Frederick M. Ausubel Huajian Gao Wooseong Kim |
| author_facet | Hee Young Heo Guijin Zou Seongeun Baek Jae‐Seok Kim Eleftherios Mylonakis Frederick M. Ausubel Huajian Gao Wooseong Kim |
| author_sort | Hee Young Heo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:14:10Z |
| format | Article |
| id | doaj.art-f853eeb6525745e880a60d08b482582a |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-07T14:14:10Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-f853eeb6525745e880a60d08b482582a2024-03-06T14:04:50ZengWileyAdvanced Science2198-38442024-03-01119n/an/a10.1002/advs.202306112A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And DaptomycinHee Young Heo0Guijin Zou1Seongeun Baek2Jae‐Seok Kim3Eleftherios Mylonakis4Frederick M. Ausubel5Huajian Gao6Wooseong Kim7College of Pharmacy Graduate School of Pharmaceutical Sciences Ewha Womans University Seoul 03760 Republic of KoreaInstitute of High Performance Computing (IHPC) Agency for Science Technology and Research (A*STAR) Singapore 138632 Republic of SingaporeCollege of Pharmacy Graduate School of Pharmaceutical Sciences Ewha Womans University Seoul 03760 Republic of KoreaDepartment of Laboratory Medicine Kangdong Sacred Heart Hospital Hallym University College of Medicine Seoul 05355 Republic of KoreaDepartment of Medicine Houston Methodist Hospital Houston TX 77030 USADepartment of Molecular Biology Massachusetts General Hospital Boston MA 02114 USAInstitute of High Performance Computing (IHPC) Agency for Science Technology and Research (A*STAR) Singapore 138632 Republic of SingaporeCollege of Pharmacy Graduate School of Pharmaceutical Sciences Ewha Womans University Seoul 03760 Republic of KoreaAbstract 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.https://doi.org/10.1002/advs.202306112antibiotic resistanceantibiotic toleranceCaenorhabditis elegansmembrane‐active antimicrobialsmethylazanediyl bisacetamideMRSA |
| spellingShingle | Hee Young Heo Guijin Zou Seongeun Baek Jae‐Seok Kim Eleftherios Mylonakis Frederick M. Ausubel Huajian Gao Wooseong Kim A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin Advanced Science antibiotic resistance antibiotic tolerance Caenorhabditis elegans membrane‐active antimicrobials methylazanediyl bisacetamide MRSA |
| title | A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin |
| title_full | A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin |
| title_fullStr | A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin |
| title_full_unstemmed | A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin |
| title_short | A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin |
| title_sort | methylazanediyl bisacetamide derivative sensitizes staphylococcus aureus persisters to a combination of gentamicin and daptomycin |
| topic | antibiotic resistance antibiotic tolerance Caenorhabditis elegans membrane‐active antimicrobials methylazanediyl bisacetamide MRSA |
| url | https://doi.org/10.1002/advs.202306112 |
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