Can β-Lactam Antibiotics Be Resurrected to Combat MRSA?

Trends Microbiol. 2019 Jan;27(1):26-38. doi: 10.1016/j.tim.2018.06.005. Epub 2018 Jul 18.

Abstract

The use of β-lactam antibiotics to treat infections caused by Staphylococcus aureus has been severely compromised by the acquisition by horizontal gene transfer of a gene that encodes the β-lactam-insensitive penicillin-binding protein PBP2a. This allows methicillin-resistant S. aureus (MRSA) to proliferate in the presence of β-lactam antibiotics. Paradoxically the dependence on PBP2a for the essential transpeptidase activity in cell wall peptidoglycan biosynthesis is the 'Achilles heel' of MRSA. Compounds that disrupt the divisome, wall teichoic acid, and functional membrane microdomains act synergistically with β-lactams against MRSA. These include drugs such as statins that are widely used in human medicine. The antibiotics vancomycin and daptomycin are also synergistic with β-lactams, and combinations have been employed to treat persistent MRSA infections. An additional benefit of exposing MRSA to β-lactams could be a reduction in virulence mediated by interfering with the global regulator Agr. The mechanistic basis of synergy is discussed, and the possibility that β-lactams can be resurrected to combat MRSA infections is explored.

Publication types

  • Review

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Daptomycin / pharmacology
  • Daptomycin / therapeutic use
  • Drug Synergism*
  • Drug Therapy, Combination / methods
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology*
  • Vancomycin / pharmacology
  • Vancomycin / therapeutic use
  • beta-Lactams / pharmacology
  • beta-Lactams / therapeutic use*

Substances

  • Anti-Bacterial Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • beta-Lactams
  • Vancomycin
  • Daptomycin