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

Novel approaches to the treatment of multi-drug 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 in vitro efficacy of combinations of SPR741 with conventional antibiotics against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Of 35 antibiotics tested, the MICs of eight were reduced 32- to 8,000-fold against E. coli and K. pneumoniae in the presence SPR741. The eight antibiotics - azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampicin, and telithromycin - had diverse targets and mechanisms of action. Against A. baumannii, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin and rifampicin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multi-drug resistant or clinical isolates of E. coli and K. pneumoniae, and 17 additional A. baumannii 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 E. coli, effectively circumventing 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.

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