Mechanisms of Daptomycin Resistance in Staphylococcus aureus

Daptomycin is a calcium-dependent lipopeptide antibiotic that targets the bacterial cell membrane, leading to rapid depolarisation and cell death. Resistance in Staphylococcus aureus arises through multifactorial adaptations of the cell envelope and metabolism. Central to many resistance phenotypes are point mutations in genes encoding phospholipid biosynthesis enzymes, notably mprF, cls2 and pgsA, which alter membrane composition and charge. Gain-of-function variants of MprF increase synthesis and externalisation of lysyl-phosphatidylglycerol, augmenting the positive surface charge and reducing binding of the cationic antibiotic. Concurrently, upregulation of dltABCD enhances D-alanylation of wall teichoic acids, further repelling daptomycin-calcium complexes. Resistance is also associated with thickened cell walls through increased peptidoglycan and teichoic acid content, creating a steric barrier to drug penetration. Lipidomic analyses reveal shifts in phosphatidylglycerol and cardiolipin species, indicating remodelling of membrane microdomains that impede antibiotic insertion. Additional mechanisms include biofilm formation, which sequesters the drug, and growth-arrest-induced tolerance that depends on active cell wall remodelling. These adaptive strategies can emerge during therapy or in the absence of direct exposure, often triggered by host defence peptides. Understanding these interconnected molecular and physiological changes is vital for surveillance of resistance, optimisation of daptomycin dosing, and the design of adjunct therapies to restore antibiotic efficacy.

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Mechanisms of Daptomycin Resistance in Staphylococcus aureus publication trend

The graph below shows the total number of articles in mechanisms of daptomycin resistance in staphylococcus aureus across all publications each year (not limited to Nature Index journals).

Technical terms

Lipopeptide antibiotic: A cyclic peptide linked to a fatty acid chain that inserts into bacterial membranes, disrupting integrity.

Phosphatidylglycerol (PG): An anionic phospholipid abundant in bacterial membranes and a primary target for daptomycin binding.

Lysyl-phosphatidylglycerol (Lys-PG): A cationic derivative of PG produced by MprF that increases membrane positive charge.

Wall teichoic acid (WTA): A surface-anchored glycopolymer that contributes to cell wall charge and rigidity.

Adaptive laboratory evolution (ALE): An experimental approach in which microbes are cultured under selective pressure to accumulate adaptive mutations.

Biofilm: A structured community of bacteria embedded in an extracellular matrix that impedes antibiotic penetration.

Minimum inhibitory concentration (MIC): The lowest antibiotic concentration that prevents visible bacterial growth in vitro.

References

1. Growth Arrest of Staphylococcus aureus Induces Daptomycin Tolerance via Cell Wall Remodelling. mBio (2023).
2. Phenotypic and genetic characterization of daptomycin non-susceptible Staphylococcus aureus strains selected by adaptive laboratory evolution. Frontiers in Cellular and Infection Microbiology (2024).
3. Characterization of the Mechanisms of Daptomycin Resistance among Gram-Positive Bacterial Pathogens by Multidimensional Lipidomics. mSphere (2017).
4. Whole Genome Characterization of the Mechanisms of Daptomycin Resistance in Clinical and Laboratory Derived Isolates of Staphylococcus aureus. PLOS ONE (2012).
5. Phenotypic and Genotypic Characterization of Daptomycin-Resistant Methicillin-Resistant Staphylococcus aureus Strains: Relative Roles of mprF and dlt Operons. PLOS ONE (2014).
6. Increased Cell Wall Teichoic Acid Production and D-alanylation Are Common Phenotypes among Daptomycin-Resistant Methicillin-Resistant Staphylococcus aureus (MRSA) Clinical Isolates. PLOS ONE (2013).
7. Gain-of-Function Mutations in the Phospholipid Flippase MprF Confer Specific Daptomycin Resistance. mBio (2018).
8. Emergence of Daptomycin Resistance in Daptomycin-Naïve Rabbits with Methicillin-Resistant Staphylococcus aureus Prosthetic Joint Infection Is Associated with Resistance to Host Defense Cationic Peptides and mprF Polymorphisms. PLOS ONE (2013).