Designing a leucine-rich antibacterial nonapeptide with potent activity against mupirocin-resistant MRSA via a structure-activity relationship study

Chem Biol Drug Des. 2021 Jun;97(6):1185-1193. doi: 10.1111/cbdd.13840. Epub 2021 Apr 5.

Abstract

Staphylococcus aureus is the main aetiological agent responsible for the majority of human skin infections. Of particular concern is the methicillin-resistant variety, commonly known as MRSA. The extensive use of the first-line topical antibiotic of choice, mupirocin, has inevitably resulted in the emergence of resistant strains, signalling an urgent need for the development of new antibacterials with new mechanisms of action. In this work, we describe how we designed a novel cationic nonapeptide, containing only leucine and two lysine residues, with potent anti-MRSA activity and a rapid bactericidal mode of action. Coupled to a favourable safety profile towards human skin fibroblasts, we believe nonapeptide 11 has high potential for further development as a mupirocin replacement candidate to treat skin infections caused by MRSA.

Keywords: MRSA; antibacterial peptide; antimicrobial peptide; mupirocin; skin infection; topical antibiotic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cell Survival / drug effects
  • Drug Design*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Microbial Sensitivity Tests
  • Mupirocin / pharmacology
  • Nanostructures / chemistry*
  • Peptides / chemistry*
  • Peptides / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Peptides
  • Mupirocin