Chimeric protein-protein interface inhibitors allow efficient inhibition of type III secretion machinery and virulence

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dc.creatorTuan-Dung Ngo
dc.creatorSophie Plé
dc.creatorAline Thomas
dc.creatorCaroline Barette
dc.creatorAntoine Fortuné
dc.creatorYounes Bouzidi
dc.creatorMarie-Odile Fauvarque
dc.creatorRossimiriam Pereira de Freitas
dc.creatorFlaviane Francisco Hilário
dc.creatorIna Attrée
dc.creatorYung-Sing Wong
dc.creatorEric Faudry
dc.date.accessioned2024-02-08T17:34:34Z
dc.date.accessioned2025-09-08T23:05:46Z
dc.date.available2024-02-08T17:34:34Z
dc.date.issued2019
dc.description.sponsorshipOutra Agência
dc.identifier.doihttps://doi.org/10.1021/acsinfecdis.9b00154
dc.identifier.issn2373-8227
dc.identifier.urihttps://hdl.handle.net/1843/63872
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofACS Infectious Diseases
dc.rightsAcesso Restrito
dc.subjectMoléculas
dc.subjectToxicidade - Testes
dc.subjectPseudomonas aeruginosa
dc.subjectAgentes antivirais
dc.subjectDrogas - Resistência em microorganismos
dc.subject.otherType III secretion system
dc.subject.otherAntivirulence
dc.subject.otherBacterial resistance
dc.subject.otherProtein−protein interface inhibitors
dc.subject.otherHybrid molecules
dc.subject.otherClick chemistry
dc.titleChimeric protein-protein interface inhibitors allow efficient inhibition of type III secretion machinery and virulence
dc.typeArtigo de periódico
local.citation.epage1854
local.citation.issue11
local.citation.spage1843
local.citation.volume5
local.description.resumoPseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen naturally resistant to many common antibiotics and acquires new resistance traits at an alarming pace. Targeting the bacterial virulence factors by an antivirulence strategy, therefore, represents a promising alternative approach besides antibiotic therapy. The Type III secretion system (T3SS) of P. aeruginosa is one of its main virulence factors. It consists of more than 20 proteins building a complex syringe-like machinery enabling the injection of toxin into host cells. Previous works showed that disrupting interactions between components of this machinery efficiently lowers the bacterial virulence. Using automated target-based screening of commercial and in-house libraries of small molecules, we identified compounds inhibiting the protein–protein interaction between PscE and PscG, the two cognate chaperones of the needle subunit PscF of P. aeruginosa T3SS. Two hits were selected and assembled using Split/Mix/Click chemistry to build larger hybrid analogues. Their efficacy and toxicity were evaluated using phenotypic analysis including automated microscopy and image analysis. Two nontoxic hybrid leads specifically inhibited the T3SS and reduced the ex vivo cytotoxicity of bacteria and their virulence in Galleria mellonella.
local.identifier.orcidhttps://orcid.org/0000-0003-3909-3649
local.identifier.orcidhttps://orcid.org/0000-0002-4353-3531
local.identifier.orcidhttps://orcid.org/0000-0003-0999-7751
local.identifier.orcidhttps://orcid.org/0000-0003-4199-4147
local.identifier.orcidhttps://orcid.org/0000-0001-9186-7694
local.identifier.orcidhttps://orcid.org/0000-0001-5020-3701
local.identifier.orcidhttps://orcid.org/0000-0001-6974-3724
local.identifier.orcidhttps://orcid.org/0000-0002-2580-764X
local.identifier.orcidhttps://orcid.org/0000-0003-1038-9681
local.identifier.orcidhttps://orcid.org/0000-0001-9958-6029
local.publisher.countryBrasil
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://pubs.acs.org/doi/10.1021/acsinfecdis.9b00154

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