Mechanisms of drug resistance: daptomycin resistance

Ann N Y Acad Sci. 2015 Sep;1354:32-53. doi: 10.1111/nyas.12948. Epub 2015 Oct 23.

Abstract

Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction into clinical practice in 2003, DAP has become an important key frontline antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP resistance (DAP-R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp., and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP-R are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have provided novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope, such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria.

Keywords: Bacillus subtilis; Enterococcus; Staphylococcus aureus; daptomycin resistance.

Publication types

  • Review

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cell Wall / genetics
  • Cell Wall / metabolism
  • Daptomycin / pharmacology*
  • Drug Resistance, Bacterial*
  • Gram-Positive Bacteria / drug effects*
  • Gram-Positive Bacteria / genetics
  • Gram-Positive Bacteria / metabolism
  • Gram-Positive Bacterial Infections / microbiology
  • Humans
  • Mutation

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Daptomycin