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


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, the authors of this article, led by GCIR Professor Kimberly Kline, hypothesized that functional redundancy between the paralogs prevents mprF-mediated resistance and masks other evolutionary pathways to DAPR. Here, her team performed in vitro evolution to DAPR in mprF mutant background. They 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. They 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.

Full article:

Why is it important?

Enterococci, commonly found in healthcare settings, pose a significant threat due to their involvement in hospital-acquired infections. They contribute notably to infections such as catheter-associated infections and endocarditis. Enterococci's ability to form biofilms makes them resilient to antibiotics, including last-resort drugs like vancomycin. Additionally, some strains have developed resistance to daptomycin, another crucial antibiotic. Understanding the genetic mutations driving this resistance is essential. Recent research highlights mutations in specific genes associated with daptomycin resistance in enterococci, shedding light on potential targets for combating resistance. In this work, the authors discovered novel mutation targets like FtsH and HrcA, crucial for resistance acquisition, opening new avenues for potential therapeutic interventions to counter antibiotic resistance in enterococci.


4 Apr 2024