Please use this identifier to cite or link to this item: 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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