期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：38
DOI：10.1073/pnas.2123117119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Inhibiting bacterial lipoprotein biosynthesis in Enterobacteriaceae is an attractive antibacterial strategy to target multidrug resistance, and mechanisms of resistance to prolipoprotein signal peptidase (LspA) inhibitors in
Escherichia coli are relatively well understood. In contrast, it has been challenging to understand the mechanisms of resistance to LspA inhibitors in
Acinetobacter baumannii due to the substantially lower inhibitor potencies and the lack of a homologous
lpp gene. By increasing the antibacterial potency of the LspA inhibitor, globomycin, against wild-type
A. baumannii, we were able to examine resistance to LspA inhibitors, resulting in the identification of a previously uncharacterized highly abundant lipoprotein, LspA inhibitor resistance lipoprotein. This study reveals insights into resistance mechanisms of
A. baumannii against inhibitors of bacterial lipoprotein biosynthesis.
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. baumannii, we focused on inhibiting lipoprotein biosynthesis, a pathway that is essential for envelope biogenesis in gram-negative bacteria. The natural product globomycin, which inhibits the essential type II signal peptidase prolipoprotein signal peptidase (LspA), is ineffective against wild-type
A. baumannii clinical isolates due to its poor penetration through the outer membrane. Here, we describe a globomycin analog, G5132, that is more potent against wild-type and clinical
A. baumannii isolates. Mutations leading to G5132 resistance in
A. baumannii map to the signal peptide of a single hypothetical gene, which we confirm encodes an alanine-rich lipoprotein and have renamed
lirL (prolipoprotein signal peptidase inhibitor resistance lipoprotein). LirL is a highly abundant lipoprotein primarily localized to the inner membrane. Deletion of
lirL leads to G5132 resistance, inefficient cell division, increased sensitivity to serum, and attenuated virulence. Signal peptide mutations that confer resistance to G5132 lead to the accumulation of diacylglyceryl-modified LirL prolipoprotein in untreated cells without significant loss in cell viability, suggesting that these mutations overcome a block in lipoprotein biosynthetic flux by decreasing LirL prolipoprotein substrate sensitivity to processing by LspA. This study characterizes a lipoprotein that plays a critical role in resistance to LspA inhibitors and validates lipoprotein biosynthesis as a antibacterial target in
A. baumannii.
