An essential protease, FtsH, influences daptomycin resistance acquisition in Enterococcus faecalis

Area of Science:

• Microbiology
• Molecular Biology
• Antimicrobial Resistance

Background:

• Daptomycin is a critical antibiotic for treating vancomycin-resistant Enterococci.
• Rapid daptomycin resistance (DAP^R) evolution limits treatment options.
• The role of Enterococcus faecalis mprF paralogs in DAP^R is unclear.

Purpose of the Study:

• Investigate the role of mprF in DAP^R acquisition in Enterococcus faecalis.
• Identify genetic factors influencing the speed of DAP^R evolution.
• Explore novel anti-resistance strategies.

Main Methods:

• Performed in vitro evolution to DAP^R in an mprF mutant background.
• Analyzed genetic mutations associated with resistance.
• Assessed the essentiality and function of FtsH and HrcA.

Main Results:

• Absence of mprF significantly slowed DAP^R evolution.
• Inactivating mutations in ftsH were associated with slowed DAP^R.
• FtsH depletion led to growth impairment, reduced extracellular acidification, and impaired metabolic reduction.
• FtsH is essential in the parental strain but not in the ΔmprF strain.

Conclusions:

• Functional redundancy of mprF paralogs may mask other DAP^R pathways.
• FtsH and HrcA are critical for DAP^R evolution and cellular processes.
• Targeting FtsH and HrcA presents a promising strategy to combat daptomycin resistance.