{
  "abstract": "Bacterial cell division requires precise regulation of septal peptidoglycan (PG) synthesis by the essential SEDS-bPBP synthase FtsWI. Activation of FtsWI is thought to occur through an allosteric cascade initiated by the late-arriving divisome protein FtsN and transmitted via the FtsQ-FtsL-FtsB (FtsQLB) complex, but the molecular details of this process remain incompletely defined and differ across species. Here, using the conditional essentiality of ftsN in Pseudomonas aeruginosa, we identify substitutions in the non-enzymatic pedestal domain of FtsI that bypass the requirement for FtsN. These mutations restore cell division in ΔftsN cells, suppress dominant-negative phenotypes of activation-defective ftsL alleles, and reduce cell length in an otherwise wild-type background, demonstrating that they alter FtsWI regulation to overcome the requirement for stimulation by both FtsN and FtsQLB. Mapping these mutations onto the P. aeruginosa FtsQLBWI structure reveals that they cluster on distinct surfaces of the pedestal domain. Because some of these substitutions have been identified in clinical P. aeruginosa isolates with increased aztreonam resistance, we next asked whether these regulatory substitutions alter β-lactam susceptibility. Variants at the FtsI-FtsL interface modestly reduce susceptibility to multiple β-lactam antibiotics, whereas a variant on the opposite face of the pedestal domain produces striking FtsN-dependent hypersusceptibility to the same molecules. These findings show that the FtsI pedestal domain plays a central role in the regulation of FtsWI and reveal a previously unrecognized relationship between divisome regulation and β-lactam susceptibility. More broadly, our work identifies the pedestal domain as a regulatory hub that integrates multiple inputs controlling septal PG synthesis and highlights its potential relevance to β-lactam resistance in clinical P. aeruginosa isolates. Author summary: Bacterial cell division is driven by the coordinated activation of septal peptidoglycan synthesis, but the regulatory mechanisms that govern this process remain poorly understood. Here we identify mutations in the non-enzymatic pedestal domain of the septal transpeptidase FtsI that bypass the requirement for the activation factor FtsN in Pseudomonas aeruginosa. These substitutions reveal that the pedestal domain integrates regulatory inputs from both FtsN and the FtsQLB complex to control FtsWI activation. Notably, substitutions at the FtsI-FtsL interface modestly reduce susceptibility to multiple β-lactam antibiotics that specifically target FtsI, whereas a mutation on the opposite face renders P. aeruginosa hypersusceptible to these agents. These findings uncover a previously unrecognized link between divisome regulation and β-lactam susceptibility and suggest that altered activation of septal peptidoglycan biosynthesis represents a noncanonical contributor to antibiotic resistance in P. aeruginosa.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada",
    "Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jake Colautti"
    },
    {
      "affs": [
        1
      ],
      "name": "Alexander C. Anderson"
    },
    {
      "name": "Wyatt P. K. Clark"
    },
    {
      "name": "Lindsey S. Marmont"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/54eytjv7reag4.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pgen.1012319",
  "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012319",
  "id": "54eytjv7reag4",
  "issns": [
    "1553-7404"
  ],
  "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012319",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Bacterial Genetics and Biotechnology"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Enzymology/Enzymes/Transferases/Glycosyltransferases"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Enzymes/Transferases/Glycosyltransferases"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell cycle and cell division"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genetic loci"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Mutation/Substitution mutation"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Bacterial pathogens/Escherichia coli"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Bacterial pathogens/Pseudomonas aeruginosa"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Microbial control/Antimicrobials/Antibiotics"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Enterobacteriaceae/Escherichia/Escherichia coli"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Gut bacteria/Escherichia/Escherichia coli"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Pseudomonas/Pseudomonas aeruginosa"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Bacterial pathogens/Escherichia coli"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Bacterial pathogens/Pseudomonas aeruginosa"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pharmacology/Drugs/Antimicrobials/Antibiotics"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical compounds/Organic compounds/Carbohydrates/Disaccharides/Sucrose"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Organic chemistry/Organic compounds/Carbohydrates/Disaccharides/Sucrose"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Escherichia coli"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Prokaryotic models/Escherichia coli"
    ],
    [
      "plos",
      "/Research and analysis methods/Model organisms/Escherichia coli"
    ]
  ],
  "openalex": "W7214636380",
  "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012319&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-28",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/54eytjv7reag4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:37Z",
      "native_id": "10.1371/journal.pgen.1012319",
      "source": "plos",
      "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012319"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
    },
    {
      "field": "biology",
      "origin": "plos:microbiology",
      "subfield": "microbiology"
    }
  ],
  "title": "Altered regulation of septal peptidoglycan synthesis modulates β-lactam susceptibility in Pseudomonas aeruginosa",
  "title_text": "Altered regulation of septal peptidoglycan synthesis modulates β-lactam susceptibility in Pseudomonas aeruginosa",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:37Z",
  "url": "https://research.draconitic.com/paper/54eytjv7reag4",
  "venue": "PLOS Genetics",
  "versions": []
}