Mechanism of Action and Resistance to Daptomycin in Staphylococcus aureus and Enterococci

Abstract

Lipopeptides are natural product antibiotics that consist of a peptide core with a lipid tail with a diverse array of target organisms and mechanisms of action. Daptomycin (DAP) is an example of these compounds with specific activity against Gram-positive organisms. DAP has become increasingly important to combat infections caused by Gram-positive bacteria because of the presence of multidrug resistance in these organisms, particularly in methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). However, emergence of resistance to DAP during therapy is a well-described phenomenon that threatens the clinical use of this antibiotic, limiting further the therapeutic options against both MRSA and VRE. This work will review the historical aspects of the development of DAP, as well as the current knowledge on its mechanism of action and pathways to resistance in a clinically relevant context.

Figure 1.

Structure of daptomycin and organization of the daptomycin biosynthesis gene cluster in Streptomyces filamentosus. (A) Chemical structure of daptomycin (DAP) with noncanonical amino acids and N-decanoyl fatty acid tail labeled. l-Kyn, l-Kynurenine; l-Orn, l-Ornithine; d-MeOGlu, d-3-methylglutamic acid. (B) Organization of the DAP biosynthesis gene cluster (see text for details). (Sequence information from NCBI database, accession number AY787762.1.)

Figure 2.

Proposed mechanisms for the action of daptomycin. In solution, daptomycin (DAP) complexes with calcium to form small micelles, and subsequent membrane insertion is dependent on both the presence of calcium and phosphatidylglycerol (PG). Once inserted, DAP oligomerizes and transitions to the inner membrane leaflet. These complexes then align on opposite sides of the membrane to form a pore channel permeable to small cations, or disrupt membrane integrity by extracting lipids and leading to transient ion leakage.

Figure 3.

Strategies for resisting daptomycin membrane attack. (A) Repulsion: In Staphylococcus aureus and Enterococcus faecium, changes in cell-surface charge and membrane phospholipid content block daptomycin (DAP) membrane association and oligomerization. (B) Diversion: In E. faecalis sensitive to DAP cardiolipin (CL) clusters at the division septum. In resistant isolates, redistribution of CL microdomains “traps” DAP away from the septum. ML, membrane lipid; LPG, lysylphosphatidylglycerol.