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While genetic determinants associated with clinical daptomycin resistance (DAP<jats:sup>R<\/jats:sup>) have been described, information on factors affecting the speed of DAP<jats:sup>R<\/jats:sup>acquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol\u2010modifying enzyme involved in cationic antimicrobial resistance, is linked to DAP<jats:sup>R<\/jats:sup>in pathogens such as methicillin\u2010resistant<jats:italic>Staphylococcus aureus<\/jats:italic>. Since<jats:italic>Enterococcus faecalis<\/jats:italic>encodes two paralogs of<jats:italic>mprF<\/jats:italic>and clinical DAP<jats:sup>R<\/jats:sup>mutations do not map to<jats:italic>mprF<\/jats:italic>, we hypothesized that functional redundancy between the paralogs prevents<jats:italic>mprF<\/jats:italic>\u2010mediated resistance and masks other evolutionary pathways to DAP<jats:sup>R<\/jats:sup>. Here, we performed in\u00a0vitro evolution to DAP<jats:sup>R<\/jats:sup>in<jats:italic>mprF<\/jats:italic>mutant background. We discovered that the absence of<jats:italic>mprF<\/jats:italic>results in slowed DAP<jats:sup>R<\/jats:sup>evolution and is associated with inactivating mutations in<jats:italic>ftsH<\/jats:italic>, resulting in the depletion of the chaperone repressor HrcA. We also report that<jats:italic>ftsH<\/jats:italic>is essential in the parental, but not in the \u0394<jats:italic>mprF<\/jats:italic>, 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\u2010resistance strategies.<\/jats:p>","DOI":"10.1111\/mmi.15253","type":"journal-article","created":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T01:59:58Z","timestamp":1711418398000},"page":"1021-1038","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["An essential protease,<scp>FtsH<\/scp>, influences daptomycin resistance acquisition in<i>Enterococcus faecalis<\/i>"],"prefix":"10.1111","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9662-4958","authenticated-orcid":false,"given":"Zeus Jaren","family":"Nair","sequence":"first","affiliation":[{"name":"Singapore\u2010MIT Alliance for Research and Technology, Antimicrobial Drug Resistance Interdisciplinary Research Group Singapore Singapore"},{"name":"Singapore Centre for Environmental Life Sciences Engineering Nanyang Technological University Singapore 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