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

To address the growing resistance of Gram-negative bacteria and enhance the clinical application potential of antimicrobial peptides. In this study, we combined two alpha-helical antimicrobial peptides K-4 (WRKWRKWRKWRK-NH2) or K-5 (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 K-4 or K-5, 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 K-4 or K-5. 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 K-4 and K-5 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.