A Phage-Based Approach to Identify Antivirulence Inhibitors of Bacterial Type IV Pili

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dc.contributor.authorShimozono, Tori M.en
dc.contributor.authorVogelaar, Nancy J.en
dc.contributor.authorO'Hara, Megan T.en
dc.contributor.authorYang, Zhaominen
dc.date.accessioned2025-01-22T14:01:38Zen
dc.date.available2025-01-22T14:01:38Zen
dc.date.issued2025-01-17en
dc.description.abstractThe increasing threat of antibiotic resistance underscores the urgent need for innovative strategies to combat infectious diseases, including the development of antivirulants. Microbial pathogens rely on their virulence factors to initiate and sustain infections. Antivirulants are small molecules designed to target virulence factors, thereby attenuating the virulence of infectious microbes. The bacterial type IV pilus (T4P), an extracellular protein filament that depends on the T4P machinery (T4PM) for its biogenesis, dynamics and function, is a key virulence factor in many significant bacterial pathogens. While the T4PM presents a promising antivirulence target, the systematic identification of inhibitors for its multiple protein constituents remains a considerable challenge. Here we report a novel high-throughput screening (HTS) approach for discovering T4P inhibitors. It uses Pseudomonas aeruginosa, a high-priority pathogen, in combination with its T4P-targeting phage, φKMV. Screening of a library of 2168 compounds using an optimised protocol led to the identification of tuspetinib, based on its deterrence of the lysis of P. aeruginosa by φKMV. Our findings show that tuspetinib also inhibits two additional T4P-targeting phages, while having no effect on a phage that recognises lipopolysaccharides as its receptor. Additionally, tuspetinib impedes T4P-mediated motility in P. aeruginosa and Acinetobacter species without impacting growth or flagellar motility. This bacterium-phage pairing approach is applicable to a broad range of virulence factors that are required for phage infection, paving ways for the development of advanced chemotherapeutics against antibiotic-resistant infections.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1111/1751-7915.70081en
dc.identifier.eissn1751-7915en
dc.identifier.issn1751-7915en
dc.identifier.issue1en
dc.identifier.orcidYang, Zhaomin [0000-0002-2044-6793]en
dc.identifier.pmid39822166en
dc.identifier.urihttps://hdl.handle.net/10919/124301en
dc.identifier.volume18en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/39822166en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectPseudomonas aeruginosaen
dc.subjectantivirulenceen
dc.subjecthigh‐throughput screenen
dc.subjectphageen
dc.subjecttype 4 pilus (T4P)en
dc.subject.meshFimbriae, Bacterialen
dc.subject.meshPseudomonas aeruginosaen
dc.subject.meshVirulence Factorsen
dc.subject.meshAnti-Bacterial Agentsen
dc.subject.meshDrug Evaluation, Preclinicalen
dc.subject.meshHigh-Throughput Screening Assaysen
dc.titleA Phage-Based Approach to Identify Antivirulence Inhibitors of Bacterial Type IV Pilien
dc.title.serialMicrobial Biotechnologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherIMen
dc.type.otherJournal Articleen
dcterms.dateAccepted2024-12-26en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Scienceen
pubs.organisational-groupVirginia Tech/Science/Biological Sciencesen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Science/COS T&R Facultyen

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