Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741

• Published in: Antimicrobial agents and chemotherapy Vol. 61; no. 8
• Main Authors: Corbett, David, Wise, Andrew, Langley, Tara, Skinner, Kirsty, Trimby, Emily, Birchall, Stephen, Dorali, Alain, Sandiford, Stephanie, Williams, Jennifer, Warn, Peter, Vaara, Martti, Lister, Troy
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-08-2017
• Subjects: Acinetobacter baumannii - drug effects; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Antimicrobial Cationic Peptides; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Cell Membrane Permeability - drug effects; Drug Synergism; Escherichia coli - drug effects; Gram-Negative Bacteria; Gram-Negative Bacteria - drug effects; Gram-Negative Bacterial Infections; Gram-Negative Bacterial Infections - drug therapy; Gram-Negative Bacterial Infections - microbiology; Klebsiella pneumoniae - drug effects; Microbial Sensitivity Tests; Polymyxin B; Polymyxin B - pharmacology; Susceptibility; microbiology; potentiation; Gram-negative bacteria
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.00200-17

Novel approaches for the treatment of multidrug-resistant Gram-negative bacterial infections are urgently required. One approach is to potentiate the efficacy of existing antibiotics whose spectrum of activity is limited by the permeability barrier presented by the Gram-negative outer membrane. Cationic peptides derived from polymyxin B have been used to permeabilize the outer membrane, granting antibiotics that would otherwise be excluded access to their targets. We assessed the
efficacies of combinations of SPR741 with conventional antibiotics against
,
, and
Of 35 antibiotics tested, the MICs of 8 of them were reduced 32- to 8,000-fold against
and
in the presence of SPR741. The eight antibiotics, azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampin, and telithromycin, had diverse targets and mechanisms of action. Against
, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin, and rifampin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multidrug-resistant or clinical isolates of
and
and 17 additional
isolates in order to rank the potentiated antibiotics. SPR741 was also able to potentiate antibiotics that are substrates of the AcrAB-TolC efflux pump in
, effectively circumventing the contribution of this pump to intrinsic antibiotic resistance. These studies support the further development of SPR741 in combination with conventional antibiotics for the treatment of Gram-negative bacterial infections.