Inhibition of Escherichia coli Lipoprotein Diacylglyceryl Transferase Is Insensitive to Resistance Caused by Deletion of Braun’s Lipoprotein
| Autor: | Donghong Yan, Cameron L. Noland, Jingyu Diao, Peter Liu, Anand Kumar Katakam, Mike Reichelt, Haruhiko Ogawa, Cary D. Austin, Susan L. Gloor, Yutian Peng, Min Xu, Hayato Yanagida, Patrick C Reid, Jing Kang, Rie Komura, Homer Pantua, Kelly M. Storek, Yiming Xu, Michael Volny, Wendy Sandoval, Jeremy Murray, Nicholas N. Nickerson, Steven T. Rutherford, Junichi Nishikawa, Tatsuya Sano, Hiroko Inaba, Sharookh B. Kapadia, Christian N. Cunningham |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
antibiotic resistance
Lipoproteins Lpp Peptidoglycan Braun's lipoprotein medicine.disease_cause Microbiology 03 medical and health sciences Mice Bacterial Proteins Transferases medicine Escherichia coli Inner membrane Transferase Animals Aspartic Acid Endopeptidases Uropathogenic Escherichia coli Molecular Biology 030304 developmental biology 0303 health sciences biology 030306 microbiology Gene Expression Regulation Bacterial biology.organism_classification Cell biology Anti-Bacterial Agents Lgt Female Bacterial outer membrane Biogenesis Bacteria Gene Deletion Lipoprotein Research Article |
| Zdroj: | Journal of Bacteriology |
| ISSN: | 1098-5530 0021-9193 |
| Popis: | Lipoprotein diacylglyceryl transferase (Lgt) catalyzes the first step in the biogenesis of Gram-negative bacterial lipoproteins which play crucial roles in bacterial growth and pathogenesis. We demonstrate that Lgt depletion in a clinical uropathogenic Escherichia coli strain leads to permeabilization of the outer membrane and increased sensitivity to serum killing and antibiotics. Importantly, we identify G2824 as the first-described Lgt inhibitor that potently inhibits Lgt biochemical activity in vitro and is bactericidal against wild-type Acinetobacter baumannii and E. coli strains. While deletion of a gene encoding a major outer membrane lipoprotein, lpp, leads to rescue of bacterial growth after genetic depletion or pharmacologic inhibition of the downstream type II signal peptidase, LspA, no such rescue of growth is detected after Lgt depletion or treatment with G2824. Inhibition of Lgt does not lead to significant accumulation of peptidoglycan-linked Lpp in the inner membrane. Our data validate Lgt as a novel antibacterial target and suggest that, unlike downstream steps in lipoprotein biosynthesis and transport, inhibition of Lgt may not be sensitive to one of the most common resistance mechanisms that invalidate inhibitors of bacterial lipoprotein biosynthesis and transport. IMPORTANCE As the emerging threat of multidrug-resistant (MDR) bacteria continues to increase, no new classes of antibiotics have been discovered in the last 50 years. While previous attempts to inhibit the lipoprotein biosynthetic (LspA) or transport (LolCDE) pathways have been made, most efforts have been hindered by the emergence of a common mechanism leading to resistance, namely, the deletion of the gene encoding a major Gram-negative outer membrane lipoprotein lpp. Our unexpected finding that inhibition of Lgt is not susceptible to lpp deletion-mediated resistance uncovers the complexity of bacterial lipoprotein biogenesis and the corresponding enzymes involved in this essential outer membrane biogenesis pathway and potentially points to new antibacterial targets in this pathway. |
| Databáze: | OpenAIRE |
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