Poster Presentation 11th Australian Peptide Conference 2015

Re-engineering Polymyxins to Improve Their Safety and Efficacy: Development of the Next-Generation Polymyxin Antibiotics (#160)

Kade Roberts 1 2 , Jiping Wang 2 , Heidi Yu 2 , Andrew S Horne 2 , Jo-anne Pinson 2 , Lv Wang 2 , Phillip E Thompson 1 2 , Roger L Nation 2 , Jian Li 2
  1. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  2. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

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 antibiotic drugs. The cyclic lipopeptide antibiotics, polymyxin B and colistin are being used as the last-line therapy against these problematic ‘Superbugs’ [1,2]. However, the effective use of polymyxins in the clinic is hampered by their potential for nephrotoxicity. Recent clinical studies have reported 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 clinical use.[3,4,5] Furthermore, suboptimal dosing may promote the emergence of polymyxin resistance.[6]

Here we report on our polymyxin drug discovery and development program which aims to produce new polymyxins with improved safety and efficacy profiles over the current clinically available polymyxin B and colistin. Potential hit compounds based on the polymyxin core scaffold were designed using an SAR-based mechanistic model,[7] then prepared by solid-phase synthesis using our polymyxin synthesis platform. Hit compounds where identified through in vitro MIC screening against a panel of MDR Gram negative clinical isolates. To date over 500 novel polymyxin analogs have been synthesised and screened. Hits were then screened for in vivo efficacy in a mouse blood infection model and mouse nephrotoxicity model. Promising compounds where then further subjected to in vitro MIC screening against extended panels of clinical isolates and evaluation in rat and mouse pharmacokinetics models and a neutropenic mouse lung infection pharmacokinetics/pharmacodynamics model against a MDR clinical isolate. Several promising lead compounds have been identified to date with improved efficacy and significantly reduced nephrotoxicity compared to polymyxin B and colistin. The in vitro and in vivo results obtained for these lead compounds will be presented here.

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  2. Nation, R. L., Li, J., Cars, O., Couet, W., Dudley, M. N., Kaye, K. S., Mouton, J. W., Paterson, D. L., Tam, V. H., Theuretzbacher, U., Tsuji, B. T., Turnidge, J. D. (2015), Lancet. Infect. Dis. 15, 225-234.
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  4. Akajagbor, D. S., Wilson, S. L., Shere-Wolfe, K. D., Dakum, P., Charurat, M. E., Gilliam, B. L. (2013), Clin. Infect. Dis. 57, 1300-1303.
  5. Rigatto, M. H., Behle, T. F., Falci, D. R., Freitas, T., Lopes, N. T., Nunes, M., Costa, L. W., Zavascki, A. P. (2015), J. Antimicrob. Chemother. 70, 1552-1557.
  6. Dubrovskaya, Y., Chen, T. Y., Scipione, M. R., Esaian, D., Phillips, M. S., Papadopoulos, J., Mehta, S. A. (2013), Antimicrob. Agents Chemother. 5, 5394-5397.
  7. Velkov, T., Roberts, K. D., Nation, R. L., Wang, J., Thompson, P. E., Li, J. (2014), ACS Chem. Biol. 16, 1172-1117.