Mechanisms of Daptomycin Resistance in Staphylococcus aureus
Staphylococcus aureus develops resistance to daptomycin primarily through single-point mutations in the mprF gene (lysylphosphatidylglycerol synthetase), which alter bacterial cell membrane composition and charge, reducing daptomycin binding and membrane depolarization. 1
Primary Resistance Mechanism: mprF Gene Mutations
The mprF gene mutations are the most commonly identified mechanism, leading to increased production of lysyl-phosphatidylglycerol (LPG), a positively charged phospholipid 1, 2, 3, 4
These mutations cause translocation of LPG to the outer membrane leaflet, increasing the net positive surface charge of the bacterial cell 3
The increased positive charge creates electrostatic repulsion against the positively charged daptomycin molecule (which requires calcium binding), reducing drug binding to the membrane by approximately 50% compared to susceptible strains 3, 5
This reduced binding prevents daptomycin from causing its normal bactericidal effect of membrane depolarization and potassium ion leakage 6, 3
Additional Phospholipid Biosynthesis Gene Mutations
Mutations in other phospholipid biosynthesis genes beyond mprF have been identified, including cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA) 2
These mutations represent newly discovered genetic mechanisms affecting daptomycin susceptibility and alter membrane phospholipid composition 2
All daptomycin-nonsusceptible strains studied had at least one mutation in a phospholipid biosynthesis gene 2
Membrane Structural Changes
Daptomycin-resistant strains demonstrate enhanced membrane fluidity compared to susceptible parent strains 3
Resistant isolates develop a thicker cell wall, which may contribute to reduced drug penetration 2
Loss of specific membrane proteins (such as an 81 kDa membrane protein) has been observed, potentially eliminating a "chaperone" protein that facilitates daptomycin interaction with the membrane 5
These membrane alterations result in reduced susceptibility to daptomycin-induced depolarization, permeabilization, and autolysis 3
RNA Polymerase Mutations
Mutations in rpoB and rpoC genes (encoding bacterial RNA polymerase subunits) have been associated with daptomycin resistance 4
Additional mutations in regulatory genes such as walK and ggrA have been proposed as contributing factors 4
Clinical Development Pattern
Clinical isolates developing resistance during therapy average six coding region mutations across the genome, while laboratory-derived resistant strains average only two mutations 2
Resistance typically emerges during therapy in association with treatment failure, particularly in endocarditis cases 1, 3
Prior exposure to vancomycin and elevated vancomycin MICs have been associated with increases in daptomycin MICs, suggesting possible cross-resistance mechanisms 1
Important Clinical Caveat
Currently, there are no known transferable genetic elements that confer daptomycin resistance—resistance develops through spontaneous chromosomal mutations and positive selection pressure during therapy 6, 7
The heterogeneous nature of daptomycin susceptibility in initially susceptible strains may be an important factor in the development of stable, clinically relevant resistance 5
Cross-resistance to cationic antimicrobial host defense peptides (such as human neutrophil peptide-1) occurs in daptomycin-resistant strains, potentially impairing immune clearance from infection sites 3