ArticlePLoS pathogens2022
High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications.
Article in PLoS pathogens, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
26 citing papers in PubMed, 1 citations in OpenAlex.
- Polymorphisms in a bacterial signalling pathway alter evolutionary routes of antibiotic resistance in Escherichia coli.PLoS biology · 2026Article
- Development of binding and activity inhibition assays for the antibiotic resistance-associated protein PhoQ.bioRxiv : the preprint server for biology · 2026Article
- Article
- Global response to antibiotic exposure reveals a critical role for nucleotide metabolism in high-level β-lactam tolerance.npj antimicrobials and resistance · 2026Article
- Prevalence and mechanisms of high-level carbapenem antibiotic tolerance in clinical isolates of Klebsiella pneumoniae.PLoS pathogens · 2026Article
- Identification of host genetic factors modulating β-lactam resistance inEmerging microbes & infections · 2025Article
- Exogenous glutamate potentiates gentamicin to kill multidrug- and carbapenem-resistantmSystems · 2025Article
- Molecular interplay between peptidoglycan integrity and outer membrane asymmetry in maintaining cell envelope homeostasis.Journal of bacteriology · 2025Article
- Global response to antibiotic exposure uncovers a critical role for nucleotide metabolism in high-level β-lactam tolerance.Research square · 2025Article
- Effect of host microenvironment and bacterial lifestyles on antimicrobial sensitivity and implications for susceptibility testing.npj antimicrobials and resistance · 2025Review
- Alternative lipid synthesis in response to phosphate limitation promotes antibiotic tolerance in Gram-negative ESKAPE pathogens.PLoS pathogens · 2025Article
- Alternative lipid synthesis in response to phosphate limitation promotes antibiotic tolerance in Gram-negative ESKAPE pathogens.bioRxiv : the preprint server for biology · 2024Article
- Carbapenem-ResistantNanomaterials (Basel, Switzerland) · 2024Article
- Evaluation of expanded 2-aminobenzothiazole library as inhibitors of a model histidine kinase and virulence suppressors in Pseudomonas aeruginosa.Bioorganic chemistry · 2024Article
- Advancing the scale of synthetic biology via cross-species transfer of cellular functions enabled by iModulon engraftment.Nature communications · 2024Article
- DivergentmBio · 2024Article
- Identification of a novel CG307 sub-clade in third-generation-cephalosporin-resistantMicrobial genomics · 2024Article
- Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition ofbioRxiv : the preprint server for biology · 2024Article
- Growth Independent Morphometric Machine Learning Workflow for Single-Cell Antimicrobial Susceptibility Testing ofFrontiers in imaging (Lausanne, Switzerland) · 2024Article
- Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Antibiotic tolerance is an understudied potential contributor to antibiotic treatment failure and the emergence of multidrug-resistant bacteria. The molecular mechanisms governing tolerance remain poorly understood. A prominent type of β-lactam tolerance relies on the formation of cell wall-deficient spheroplasts, which maintain structural integrity via their outer membrane (OM), an asymmetric lipid bilayer consisting of phospholipids on the inner leaflet and a lipid-linked polysaccharide (lipopolysaccharide, LPS) enriched in the outer monolayer on the cell surface. How a membrane structure like LPS, with its reliance on mere electrostatic interactions to maintain stability, is capable of countering internal turgor pressure is unknown. Here, we have uncovered a novel role for the PhoPQ two-component system in tolerance to the β-lactam antibiotic meropenem in Enterobacterales. We found that PhoPQ is induced by meropenem treatment and promotes an increase in 4-amino-4-deoxy-L-aminoarabinose [L-Ara4N] modification of lipid A, the membrane anchor of LPS. L-Ara4N modifications likely enhance structural integrity, and consequently tolerance to meropenem, in several Enterobacterales species. Importantly, mutational inactivation of the negative PhoPQ regulator mgrB (commonly selected for during clinical therapy with the last-resort antibiotic colistin, an antimicrobial peptide [AMP]) results in dramatically enhanced tolerance, suggesting that AMPs can collaterally select for meropenem tolerance via stable overactivation of PhoPQ. Lastly, we identify histidine kinase inhibitors (including an FDA-approved drug) that inhibit PhoPQ-dependent LPS modifications and consequently potentiate meropenem to enhance lysis of tolerant cells. In summary, our results suggest that PhoPQ-mediated LPS modifications play a significant role in stabilizing the OM, promoting survival when the primary integrity maintenance structure, the cell wall, is removed.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.