Unstable Mechanisms of Resistance to Inhibitors of Escherichia coli Lipoprotein Signal Peptidase
Homer Pantua, Elizabeth Skippington, M. Braun, Cameron L. Noland, Jingyu Diao, Yutian Peng, Susan L. Gloor, Donghong Yan, Jing Kang, Anand Kumar Katakam, Janina Reeder, Georgette M. Castanedo, Keira Garland, László G. Kömüves, Meredith Sagolla, Cary D. Austin, Jeremy Murray, Yiming Xu, Zora Modrušan, Min Xu, Emily J. Hanan, Sharookh B. Kapadia
Abstract
Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in the clinic is not well understood, because many clinical antibiotic susceptibility testing approaches lack the resolution needed to reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor of the Escherichia coli type II signal peptidase LspA. We demonstrate that in addition to previously known mechanisms of resistance to LspA inhibitors, unstable genomic amplifications containing lspA can lead to modest yet biologically significant increases in LspA protein levels that confer a heteroresistance phenotype.