Antimicrobial peptides–antibiotics combination: An effective strategy targeting drug‐resistant Gram‐negative bacteria

Abstract To address the growing resistance of Gram‐negative bacteria and enhance the clinical application potential of antimicrobial peptides. In this study, we combined two α‐helical antimicrobial peptides K4 (WRKWRKWRKWRK‐NH2) or K5 (WRKWRKWRKWRKWRK‐NH2) with four traditional antibiotics (gentamicin, rifampicin, ciprofloxacin, and imipenem). Then we explored their potential and mechanism in inhibiting the generation of bacterial resistance. After adding K4 or K5, the tendency to produce resistant bacteria from traditional antibiotics declined significantly. And the obtained antibiotics‐resistant bacteria were further re‐sensitive to their corresponding traditional antibiotics with the addition of K4 or K5. Mostly, the combination showed synergistic or additive antibacterial effects on both the standard strains and the obtained antibiotics‐resistant bacteria, with a much better effect on the latter. Chemical sensitization and the outer membrane permeability experiments demonstrated that K4 and K5 may influence the drug efflux of the tested bacteria, while at the same time improving the outer membrane permeability of the obtained antibiotics‐resistant bacteria to traditional antibiotics by acting as a film breaker. They ultimately eliminated the generation of drug resistance. These results provided an effort that could break Gram‐negative bacteria's resistance.