Antibiotics are the “wonder drugs” of the 20th century, providing a rapid and safe therapeutic intervention against potentially fatal bacterial infections. Currently, all major classes of antibiotics are losing their clinical effectiveness due to the emergence of drug-resistant pathogens. This highlights a dire need for the renewed discovery of novel-acting antibacterial agents. The polymyxin class of antibiotics is used as a last line of defence to treat multidrug-resistant (MDR) infections but suffers from dose-limiting toxicity as well as reduced clinical effectiveness due to the global incidence of infections caused by polymyxin-resistant Gram-negative bacteria1,2. Our research aims to develop octapeptin, a new class of antibiotics that can kill polymyxin-resistant bacteria. Since their discovery over 40 years ago, no in-depth studies have been performed on octapeptin, particularly towards understanding the medicinal chemistry driving octapeptin bioactivity. This talk will focus on the structure-activity and structure-toxicity relationships of novel octapeptin analogues. We demonstrate that medicinal chemistry can lead to novel analogues with improved in vivo efficacy and in vitro cytotoxicity compared to polymyxin.
1 Meyers E, Pansy FE, Basch HI, McRipley RJ, Slusarchyk DS, Graham SF, et al. J. antibiotics. 1973, 26(8), 457-62.
2 Sugawara K, Yonemoto T, Konishi M, Matsumoto K, Miyaki T, Kawaguchi H, J. antibiotics. 1983, 36(6), 634-8.