Mechanism of Action and Resistance to Daptomycin inStaphylococcus aureusand 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 is an example of these compounds with specific activity against Gram-positive organisms. Daptomycin has become increasingly important to combat infections caused by Gram-positive bacteria due to 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 daptomycin 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 chapter will review the historical aspects of the development of daptomycin, as well as the current knowledge on its mechanism of action and pathways to resistance in a clinically relevant context.

Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis

“…These mutations are associated with a complete loss of cardiolipin and phosphatidylglycerol production (22,23). Given the critical roles of both cardiolipin and phosphatidylglycerol in the mechanism of action of DAP (24,25), it is plausible that the mutations in the loci mentioned above are the principal drivers of DAP r in our strain after in vivo passage. Of interest, this mechanism of DAP r differs substantially from the mechanisms involved in DAP r in S. aureus (charge repulsion) (26)(27)(28) and enterococci (antibiotic diversion for Enterococcus faecalis and charge repulsion for E. faecium) (29,30).…”

Experimental Evolution of Diverse Strains as a Method for the Determination of Biochemical Mechanisms of Action for Novel Pyrrolizidinone Antibiotics

“…50 E. faecalis adapted to daptomycin resistance reproducibly acquires mutations in LiaFSR, a three-component signaling system and membrane-stress response pathway (Table 4). 21,51 Similarly, B. subtilis strains frequently become daptomycin-resistant through mutations in the VraRS system, which is a signaling pathway orthologous to the E. faecalis LiaFSR pathway (Table 4).…”

Ligand‐ and Structure‐Based Approaches of Escherichia coli FabI Inhibition by Triclosan Derivatives: From Chemical Similarity to Protein Dynamics Influence

“…Daptomycin is a potent last‐resource antibiotic acting directly on the gram‐positive bacteria's membrane. Also, its resistance mechanism has been attributed to the release of decoy lipids from the pathogen that would interfere with the compound's membrane interaction . In this context, S. aureus , when infecting host tissues, may depend upon endogenous phospholipid biosynthesis to generate the decoys lipids for release .…”

“…Also, its resistance mechanism has been attributed to the release of decoy lipids from the pathogen that would interfere with the compound's membrane interaction. [24] In this context, S. aureus, when infecting host tissues, may depend upon endogenous phospholipid biosynthesis to generate the decoys lipids for release. [25] Additionally, AFN-1252, which is a potent FabI inhibitor, was shown to efficiently block daptomycin-induced phospholipid decoy production.…”