Targeting NDM-producing Klebsiella pneumoniae: Optimising novel combinations with polymyxins

New Delhi metallo-β-lactamase (NDM) producing Klebsiella pneumoniae are multidrug-resistant (MDR) and classified as an Urgent Threat by the US Centers for Disease Control and Prevention. Polymyxins remain effective as a last-line therapy for infections caused by MDR Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As polymyxin-induced nephrotoxicity is the major dose-limiting adverse effect, combination therapy with other antibiotics is warranted to preserve the efficacy of polymyxins whilst minimising the emergence of resistance. This thesis focuses on identifying novel synergistic polymyxin combinations against NDM-producing K. pneumoniae and elucidating mechanisms of synergy at the systems level.