Bactericidal antibiotics targeting lipoprotein transport in Gram-negative bacteria - Project Summary/Abstract: Our research is focused on the synthesis and biological study of antibiotics to address the growing problem of modern multi-drug resistant (MDR) pathogens of critical threat. By introducing three key structural variations within the scaffold of an established inhibitor of the localization of lipoproteins (lol) pathway, we have synthesized novel antibiotics with superior potencies against MDR Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Crucially, these more potent antibiotics induce a much lower frequency of spontaneous resistance in E. coli (FoR ~10-9) than the previously reported inhibitor (FoR ~10-7). We propose to diversify and improve the modular platform we have developed to synthesize large numbers of candidate antibiotics with improved potencies and optimized pharmacokinetic and pharmacodynamic profiles, which will be evaluated with in vitro and, where appropriate, in vivo studies. Furthermore, we aim to deepen the understanding of the mechanism of action of our molecules by cryo-EM imaging of the molecules bound to their target, the lolCD2E lipoprotein transport machinery. This will also inform structure-based design of future antibiotics candidates.
