Deletion of a previously uncharacterized lipoprotein lirL confers resistance to an inhibitor of type II signal peptidase in Acinetobacter baumannii

• DOI: 10.1073/pnas.2123117119
• Publication Date: 2022-09-13T17:34:34Z
• Authors: Ke-Jung Huang; Homer Pantua; Jingyu Diao; Elizabeth Skippin...; Michael Volny; Wendy Sandoval; Varnesh Tiku; Yutian Peng; Meredith Sagolla; Donghong Yan; Jing Kang; Anand Kumar Katakam; Nairie Michaelian; Mike Reichelt; Man-Wah Tan; Cary D. Austin; Min Xu; Emily Hanan; Sharookh B. Kapadia
• Keywords: Acinetobacter baumannii; Cell envelope

Acinetobacter baumannii is a clinically important, predominantly health care–associated gram-negative bacterium with high rates of emerging resistance worldwide. Given the urgent need for novel antibacterial therapies against A. , we focused on inhibiting lipoprotein biosynthesis, pathway that essential envelope biogenesis in bacteria. The natural product globomycin, which inhibits type II signal peptidase prolipoprotein (LspA), ineffective wild-type clinical isolates due to its poor penetration through outer membrane. Here, describe globomycin analog, G5132, more potent and isolates. Mutations leading G5132 map peptide single hypothetical gene, confirm encodes an alanine-rich have renamed lirL (prolipoprotein inhibitor lipoprotein). LirL highly abundant primarily localized inner Deletion leads resistance, inefficient cell division, increased sensitivity serum, attenuated virulence. Signal mutations confer lead accumulation diacylglyceryl-modified untreated cells without significant loss viability, suggesting these overcome block biosynthetic flux by decreasing substrate processing LspA. This study characterizes plays critical role LspA inhibitors validates biosynthesis as target .