ArticleThe Journal of biological chemistry2013
Mutants resistant to LpxC inhibitors by rebalancing cellular homeostasis.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 71 citations in OpenAlex.
- LPS in gram-negative bacterial growth and physiology: outside but fully integrated.Microbiology and molecular biology reviews : MMBR · 2026Review
- Control of the committed step in lipopolysaccharide biosynthesis.The Journal of biological chemistry · 2026Review
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- A two-component system signaling hub controls enterococcal membrane remodeling in response to daptomycin.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Biology of novel LpxC inhibitors forMicrobiology spectrum · 2026Article
- Identification of antimicrobial resistance genes in Escherichia coli through network diffusion.The Journal of antimicrobial chemotherapy · 2026Article
- From Obscurity to Opportunity: LpxH Emerges as a Promising Antibiotic Target in the Battle against Gram-Negative Pathogens.ACS infectious diseases · 2025Review
- Evaluation of a potent LpxC inhibitor for post-exposure prophylaxis treatment of antibiotic-resistantAntimicrobial agents and chemotherapy · 2025Article
- Construction and Characterization of an lpxM-DeficientInfection and drug resistance · 2025Article
- Article
- Computer-aided drug design to generate a unique antibiotic family.Nature communications · 2024Article
- Co-ordinated assembly of the multilayered cell envelope of Gram-negative bacteria.Current opinion in microbiology · 2024Review
- Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action.Antibiotics (Basel, Switzerland) · 2023Review
- Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.Science translational medicine · 2023Article
- Analysis of the Plasmid-BasedMicrobiology spectrum · 2023Article
- Synthesis of vancomycin fluorescent probes that retain antimicrobial activity, identify Gram-positive bacteria, and detect Gram-negative outer membrane damage.Communications biology · 2023Article
- Article
- Machine learning approaches to study the structure-activity relationships of LpxC inhibitors.EXCLI journal · 2023Article
- (p)ppGpp and moonlighting RNases influence the first step of lipopolysaccharide biosynthesis inmicroLife · 2023Article
- Analysis of the Plasmid-BasedApplied and environmental microbiology · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
LpxC, the deacetylase that catalyzes the second and committed step of lipid A biosynthesis in Escherichia coli, is an essential enzyme in virtually all gram-negative bacteria and is one of the most promising antibiotic targets for treatment of multidrug-resistant gram-negative infections. Despite the rapid development of LpxC-targeting antibiotics, the potential mechanisms of bacterial resistance to LpxC inhibitors remain poorly understood. Here, we report the isolation and biochemical characterization of spontaneously arising E. coli mutants that are over 200-fold more resistant to LpxC inhibitors than the wild-type strain. These mutants have two chromosomal point mutations that account for resistance additively and independently; one is in fabZ, a dehydratase in fatty acid biosynthesis; the other is in thrS, the Thr-tRNA ligase. For both enzymes, the isolated mutations result in reduced enzymatic activities in vitro. Unexpectedly, we observed a decreased level of LpxC in bacterial cells harboring fabZ mutations in the absence of LpxC inhibitors, suggesting that the biosyntheses of fatty acids and lipid A are tightly regulated to maintain a balance between phospholipids and lipid A. Additionally, we show that the mutation in thrS slows protein production and cellular growth, indicating that reduced protein biosynthesis can confer a suppressive effect on inhibition of membrane biosynthesis. Altogether, our studies reveal a previously unrecognized mechanism of antibiotic resistance by rebalancing cellular homeostasis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.