Synergistic microbicidal effect of cationic antimicrobial peptides and teicoplanin against planktonic and biofilm-encased Staphylococcus aureus

Int J Antimicrob Agents. 2019 Feb;53(2):143-151. doi: 10.1016/j.ijantimicag.2018.10.002. Epub 2018 Oct 10.

Abstract

Antibiotic resistance and biofilm formation are the main reasons for failure in treatment of bacterial infections. This study aimed to identify synergistic combinations of conventional antibiotics and novel synthetic antimicrobial and antibiofilm peptides (SAAPs) inspired by the structures of the natural human cationic peptides LL-37 and thrombocidin-1 (TC-1). The LL-37-inspired lead peptide SAAP-148 was combined with antibiotics of different classes against Staphylococcus aureus, and showed synergy with teicoplanin. Synergy with teicoplanin was also observed with LL-37, the LL-37-inspired SAAP-276 and the TC-1-inspired TC84. Interestingly, no synergy was observed against Staphylococcus epidermidis. Furthermore, teicoplanin combined with SAAP-148 or SAAP-276 showed strong interaction against S. aureus biofilms. The dltABCD operon and the mprF gene in S. aureus conferred resistance to LL-37, but SAAP-148 proved to be indifferently potent against wild-type, ΔdltA and ΔmprF S. aureus strains. When used alone, relatively high concentrations of both LL-37 and teicoplanin (30-120 µM and 4-32 mg/L, respectively) were required to kill S. aureus. Resistance to LL-37 in S. aureus was overcome by combined use of teicoplanin and LL-37. Thus, teicoplanin potentiates peptide LL-37, enhancing the efficacy of the innate defence, and combining the novel peptides with teicoplanin offers potential for enhanced efficacy of treatment of S. aureus infections, including biofilms.

Keywords: Biofilms; LL-37; Staphylococcus aureus; Synergy; Synthetic antimicrobial and antibiofilm peptides (SAAPs); Teicoplanin.

MeSH terms

  • Aminoacyltransferases / genetics
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Bacterial Proteins / genetics
  • Biofilms / growth & development*
  • Carrier Proteins / genetics
  • Drug Combinations
  • Drug Synergism
  • Membrane Transport Proteins / genetics
  • Microbial Sensitivity Tests
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / growth & development
  • Staphylococcus epidermidis / drug effects
  • Staphylococcus epidermidis / growth & development
  • Teicoplanin / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Bacterial Proteins
  • Carrier Proteins
  • D-alanyl carrier protein, bacteria
  • DltB protein, Staphylococcus
  • Drug Combinations
  • Membrane Transport Proteins
  • ropocamptide
  • Teicoplanin
  • Aminoacyltransferases
  • mprF protein, Staphylococcus aureus