ArticleNature communications2023
Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- Evaluation of the antimicrobial and antibiofilm activities of aztreonam-avibactam against the Burkholderia cepacia complex.Folia microbiologica · 2026Article
- Case Commentary: When susceptibility is not enough in recurrentAntimicrobial agents and chemotherapy · 2026Article
- From Host-Derived Pressures to the Environmental Anti-Antimicrobial Peptides Resistome: Mechanisms, Reservoirs and Implications for Therapeutic Peptide Design.Marine drugs · 2026Review
- In vitro susceptibility ofNew microbes and new infections · 2025Review
- Biocides as drivers of antibiotic resistance: A critical review of environmental implications and public health risks.Environmental science and ecotechnology · 2025Review
- Integrating bacterial molecular genetics with chemical biology for renewed antibacterial drug discovery.The Biochemical journal · 2024Review
- Cell envelope structural and functional contributions to antibiotic resistance inJournal of bacteriology · 2024Article
- The mechanism of action of auranofin analogs inMicrobiology spectrum · 2024Article
- Drug Discovery in the Field of β-Lactams: An Academic Perspective.Antibiotics (Basel, Switzerland) · 2024Review
- CRISPRi-Mediated Silencing ofJournal of proteome research · 2023Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.
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