| Title: |
Genetic Correlates of Synergy Mechanisms of Daptomycin Plus Fosfomycin in Daptomycin-Susceptible and -Resistant Methicillin-Resistant Staphylococcus aureus (MRSA) |
| Authors: |
Rose, WE; Ersoy, SC; Abdelhady, W; Dominguez, AR; Muyah Manna, JN; Artaza, JN; Mishra, R; Elsayed, AM; Proctor, RA; Baines, SL; Howden, BP; Mishra, NN |
| Publisher Information: |
MDPI AG |
| Publication Year: |
2025 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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 mprF 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 mprF (L826F) only in the DAP monotherapy arm. Interestingly, passage in FOF alone or DAP + FOF prevented the emergence of this mprF 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 lrgAB and sdrE and increased the expression level of fosB. In a rabbit infective endocarditis (IE) model, the DAP-R CB185 strain treated with DAP +/- FOF showed significantly reduced lrgB 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2076-2607 |
| Relation: |
pii: microorganisms13071532; https://hdl.handle.net/11343/363218 |
| Availability: |
https://hdl.handle.net/11343/363218 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.2C8DE3BF |
| Database: |
BASE |