Genetic Correlates of Synergy Mechanisms of Daptomycin Plus Fosfomycin in Daptomycin-Susceptible and -Resistant Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA)

Genetic Correlates of Synergy Mechanisms of Daptomycin Plus Fosfomycin in Daptomycin-Susceptible and -Resistant Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA)

This study elucidates potential genetic determinants and mechanisms involved in the synergistic effects of daptomycin (DAP) + fosfomycin (FOF) combination therapy. Among 33 clinically derived DAP-susceptible (S)/DAP-resistant (R) isogenic strain pairs, mutations in the <i>mprF</i> gene o...

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Main Authors: Warren E. Rose, Selvi C. Ersoy, Wessam Abdelhady, Alan R. Dominguez, Jedidiah Ndam Muyah Manna, Jorge N. Artaza, Reetakshi Mishra, Ahmed M. Elsayed, Richard A. Proctor, Sarah L. Baines, Benjamin P. Howden, Nagendra N. Mishra
Format: Article
Language:English
Published: MDPI AG 2025-06-01
Series:Microorganisms
Subjects:
MRSA
daptomycin
fosfomycin
combination therapy
transcriptomics
Online Access:https://www.mdpi.com/2076-2607/13/7/1532
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Summary:This study elucidates potential genetic determinants and mechanisms involved in the synergistic effects of daptomycin (DAP) + fosfomycin (FOF) combination therapy. Among 33 clinically derived DAP-susceptible (S)/DAP-resistant (R) isogenic strain pairs, mutations in the <i>mprF</i> gene occurred in 30/33 DAP-R strains, including polymorphisms of L826F (33%) or T345A/L/I (15%). Strain variants of DAP-S CB1483 serially passaged in vitro for 10 days in DAP +/− FOF identified a key non-synonymous mutation in <i>mprF</i> (L826F) only in the DAP monotherapy arm. Interestingly, passage in FOF alone or DAP + FOF prevented the emergence of this <i>mprF</i> mutation following 10-day passage. This L826F mprF polymorphism, associated with a “gain-in-function” phenotype, exhibited increased amounts of lysyl-phosphatidylglycerol (L-PG) in the cell membrane (CM). Transcriptomics revealed a relatively modest number (~10) of distinct genes that were significantly up- or downregulated (≥2 log fold) in both the DAP-S and DAP-R strain pairs upon DAP + FOF exposures (vs. DAP or FOF alone). Of note, DAP + FOF decreased expression of <i>lrgAB</i> and <i>sdrE</i> and increased the expression level of <i>fosB</i>. In a rabbit infective endocarditis (IE) model, the DAP-R CB185 strain treated with DAP +/− FOF showed significantly reduced <i>lrgB</i> expression in vegetations compared with DAP treatment alone. Overall, these findings indicate that DAP + FOF therapy impacts MRSA through multiple specific mechanisms, enhancing bacterial clearance.
ISSN:2076-2607

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