Candice Lim, Geoffrey W. Coombs, Shakeel Mowlaboccus
• Daptomycin is a drug of last-resort used to treat infections caused by multidrug-resistant gram-positive bacteria including methicillin-resistant Staphylococcus aureus • Reports of daptomycin resistance in S. aureus has increased globally • Mechanisms of daptomycin resistance in S. aureus typically involves modifications in proteins regulating lysyl phosphatidyl glycerol synthesis which in turn are regulated by two-component systems • Peptidoglycan modifications may hamper the activities of penicillin-binding proteins conferring daptomycin and β-lactam see-saw effect • Daptomycin tolerance in S. aureus is a precursor to daptomycin resistance • Daptomycin tolerance is typically exhibited by small colony variants and in biofilms Daptomycin is a cyclic lipopeptide antimicrobial used against gram-positive pathogens, including Staphylococcus aureus . Daptomycin relies on physiological calcium to anchor onto bacterial membranes and sequester lipid II, overproducing reactive oxygen species resulting in cell death. Although daptomycin is thought to be effective against approximately 80% of S. aureus , treatment failure can arise from resistant or tolerant cells. Daptomycin-resistant S. aureus typically acquires mutations in the multiple peptide resistance factor (MprF) to overproduce cationic lysyl-phosphatidylglycerol located on the outer membrane. The increase in positive cell surface charge inhibits daptomycin binding via electrostatic repulsion. Upon exposure to higher daptomycin concentrations, S. aureus may undergo further peptidoglycan modifications to attenuate daptomycin activity. These alterations can also be driven by the crosstalk in the signal transduction systems. Furthermore, the pathways in daptomycin resistance appear to overlap with tolerance which is understudied in S. aureus . In this review, we explore the current understanding of the complex interplay of molecular mechanisms involved in daptomycin resistance and tolerance in S. aureus.