pH-Responsive Antimicrobial Peptide with Selective Killing Activity for Bacterial Abscess Therapy.

The unusual acidic pH of the abscess milieu is an adverse factor that decreases the therapeutic efficacy of traditional antibiotics. Moreover, avoiding both the undesired killing of commensal bacteria and the development of drug resistance remains difficult during abscess therapy. Hence, we synthesized a series of pH-responsive antimicrobial peptides equipped with efficient bacterial killing activity at pH 6.5 and inactivity at pH 7.4. Among the peptides, F5 exhibited outstanding pH-responsive antimicrobial activity and low toxicity. Fluorescence spectroscopy and electron microscopy illustrated that F5 killed bacteria via a membrane-disruptive mechanism at acidic pH values. Mouse cutaneous abscesses revealed that F5 was equipped with excellent therapeutic ability to reduce the bacterial load and cytokines without causing skin toxicity. In summary, this study reveals a strategy for selectively killing bacteria under the pathologic conditions of abscess sites while avoiding the elimination of commensal bacteria under normal physiological pH levels.

Amphiphilic lysine conjugated to tobramycin synergizes legacy antibiotics against wild-type and multidrug-resistant Pseudomonas aeruginosa.

Peptidomimetic modification is a common route of optimization for biologically active peptides. Previous studies in our group have shown that conjugation of amphiphilic tobramycin to other antibacterials enhance their latent outer membrane permeabilizing and efflux blocking activity toward Gram-negative pathogens including Pseudomonas aeruginosa. Herein, we describe the antimicrobial adjuvant properties of amphiphilic lysine ligated to tobramycin. The most potent amphiphilic lysine-tobramycin conjugate 3 potentiated the antibacterial efficacy of 8 clinically used antibiotics against wild type, multidrug- and extensively drug-resistant P. aeruginosa isolates from Canadian hospitals whereas amphiphilic lysine 4 did not. Antibiotics that are synergistic with conjugate 3 included moxifloxacin, ciprofloxacin, erythromycin, chloramphenicol, trimethoprim, novobiocin, linezolid, and fosfomycin. Out of these 8 antibiotics, novobiocin showed highest synergy.