The emergence of multi-drug resistant (MDR) Gram-negative bacterial pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae has become a major global health issue. This problem has been further compounded by the lack of development of new antibiotics targeting these Gram-negative bacteria. This has forced clinicians to resort to using ‘old’ antibiotics such as the cyclic lipopeptides, polymyxin B and colistin as last-line therapy against these problematic ‘superbugs’ [1,2]. However, the effective use of these antibiotic peptides in the clinic is significantly hampered by their potential for nephrotoxicity. Recent clinical studies have shown that polymyxin-associated nephrotoxicity can occur in up to 60% of patients when administered intravenously and is the major dose-limiting factor for their optimal use [3,4,5]. This can lead to suboptimal dosing of the polymyxins, which can increase the risk of death and promote polymyxin resistance [6,7].
In this presentation we report on our ongoing pre-clinical polymyxin drug development program, a National Institutes of Health (NIH) funded joint academic-industry collaboration between Monash University and The Medicines Company (USA) [8]. This program aims to produce new polymyxin peptide clinical candidates with improved safety and efficacy over the currently used drugs, polymyxin B and colistin. Aspects of our novel drug design strategy and lead optimization studies will be discussed. To date a number of promising lead candidates have been identified with significantly improved safety profiles and are being progressed towards clinical evaluation.