OVERCOMING INTRINSIC AND ACQUIRED ANTIBIOTIC RESISTANCE WITH OUTER MEMBRANE PERTURBATION

Abstract

There is an urgent need to identify novel antibiotics for multidrug-resistant Gram-negative pathogens. These bacteria are intrinsically resistant to many antimicrobials due to a formidable outer membrane barrier. Herein we investigate the potential of perturbing the outer membrane to sensitize Gram-negative bacteria to otherwise inactive antibiotics. In chapter 2, we identify the ability of mcr-1 mediated resistance to confer protection from the lytic but not outer membrane-perturbing activity of colistin. Exploiting this sensitivity, we show that colistin and clarithromycin in combination are efficacious against mcr-1-expressing Klebsiella pneumoniae in murine infection models. This demonstrates the viability of colistin combination therapies against Gram-negative pathogens harbouring mcr-1, and points to a mechanism of mcr-1-mediated resistance extending beyond the predicted reduction in binding affinity of polymyxins to the outer membrane. We continue to investigate the potential of using outer membrane perturbants with otherwise inactive antimicrobials in chapter 3. In this work, we identify the ability of OM disruption to change the rules of Gram-negative entry, render pre-existing resistance ineffective, reduce the development of spontaneous resistance and attenuate biofilm formation. Together, these data suggest that OM disruption overcomes many traditional hurdles encountered during antibiotic treatment and is a high priority approach for further development.