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https://hdl.handle.net/10356/180062
Title: | An essential protease, FtsH, influences daptomycin resistance acquisition in Enterococcus faecalis | Authors: | Nair, Zeus Jaren Gao, Iris Hanxing Firras, Aslam Chong, Kelvin Kian Long Hill, Eric Choo, Pei Yi Colomer-Winter, Cristina Chen, Qingyan Manzano, Caroline Pethe, Kevin Kline, Kimberly A. |
Keywords: | Medicine, Health and Life Sciences | Issue Date: | 2024 | Source: | Nair, Z. J., Gao, I. H., Firras, A., Chong, K. K. L., Hill, E., Choo, P. Y., Colomer-Winter, C., Chen, Q., Manzano, C., Pethe, K. & Kline, K. A. (2024). An essential protease, FtsH, influences daptomycin resistance acquisition in Enterococcus faecalis. Molecular Microbiology, 121(5), 1021-1038. https://dx.doi.org/10.1111/mmi.15253 | Project: | MOE2017-T1- 001-269 MOH-000645 CREATE |
Journal: | Molecular Microbiology | Abstract: | Daptomycin is a last-line antibiotic commonly used to treat vancomycin-resistant Enterococci, but resistance evolves rapidly and further restricts already limited treatment options. While genetic determinants associated with clinical daptomycin resistance (DAPR) have been described, information on factors affecting the speed of DAPR acquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol-modifying enzyme involved in cationic antimicrobial resistance, is linked to DAPR in pathogens such as methicillin-resistant Staphylococcus aureus. Since Enterococcus faecalis encodes two paralogs of mprF and clinical DAPR mutations do not map to mprF, we hypothesized that functional redundancy between the paralogs prevents mprF-mediated resistance and masks other evolutionary pathways to DAPR. Here, we performed in vitro evolution to DAPR in mprF mutant background. We discovered that the absence of mprF results in slowed DAPR evolution and is associated with inactivating mutations in ftsH, resulting in the depletion of the chaperone repressor HrcA. We also report that ftsH is essential in the parental, but not in the ΔmprF, strain where FtsH depletion results in growth impairment in the parental strain, a phenotype associated with reduced extracellular acidification and reduced ability for metabolic reduction. This presents FtsH and HrcA as enticing targets for developing anti-resistance strategies. | URI: | https://hdl.handle.net/10356/180062 | ISSN: | 0950-382X | DOI: | 10.1111/mmi.15253 | Schools: | School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Interdisciplinary Graduate School (IGS) |
Organisations: | Singapore-MIT Alliance for Research and Technology National Centre for Infectious Diseases, Singapore |
Research Centres: | Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) | Rights: | © 2024 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | SBS Journal Articles |
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