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The mycobacterium tuberculosis outer membrane channel protein CpnT confers susceptibility to toxic molecules

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dc.contributor.authorDanilchanka, Olga
dc.contributor.authorPires, David
dc.contributor.authorAnes, Elsa
dc.contributor.authorNiederweis, Michael
dc.date.accessioned2022-05-26T15:35:18Z
dc.date.available2022-05-26T15:35:18Z
dc.date.issued2015
dc.description© 2015 American Society for Microbiology.pt_PT
dc.description.abstractMycobacterium tuberculosis, the causative agent of tuberculosis, is protected from toxic solutes by an effective outer membrane permeability barrier. Recently, we showed that the outer membrane channel protein CpnT is required for efficient nutrient uptake by M. tuberculosis and Mycobacterium bovis BCG. In this study, we found that the cpnT mutant of M. bovis BCG is more resistant than the wild type to a large number of drugs and antibiotics, including rifampin, ethambutol, clarithromycin, tetracycline, and ampicillin, by 8- to 32-fold. Furthermore, the cpnT mutant of M. bovis BCG was 100-fold more resistant to nitric oxide, a major bactericidal agent required to control M. tuberculosis infections in mice. Thus, CpnT constitutes the first outer membrane susceptibility factor in slow-growing mycobacteria. The dual functions of CpnT in uptake of nutrients and mediating susceptibility to toxic molecules are reflected in macrophage infection experiments: while loss of CpnT was detrimental for M. bovis BCG in macrophages that enable bacterial replication, presumably due to inadequate nutrient uptake, it conferred a survival advantage in macrophages that mount a strong bactericidal response. Importantly, the cpnT gene showed a significantly higher density of nonsynonymous mutations in drug-resistant clinical M. tuberculosis strains, indicating that CpnT is under selective pressure in human tuberculosis and/or during chemotherapy. Our results indicate that the CpnT channel constitutes an outer membrane gateway controlling the influx of nutrients and toxic molecules into slow-growing mycobacteria. This study revealed that reducing protein-mediated outer membrane permeability might constitute a new drug resistance mechanism in slow-growing mycobacteria.pt_PT
dc.description.sponsorshipThis work was supported by a Senior Research Training Fellowship from the American Lung Association to O.D., by a fellowship (SFRH/BD/63747/2009) from the National Foundation for Science FCT to D.P. and grants PIC/IC/82859/2007, PTDC/BIA-BCM/102123/2008, and PTDC/SAU-MII/098024/2008 to E.A., and by National Institutes of Health grants AI63432, AI074805, and AI083632 to M.N.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAntimicrob Agents Chemother. 2015 Apr;59(4):2328-2336pt_PT
dc.identifier.doi10.1128/AAC.04222-14pt_PT
dc.identifier.eissn1098-6596
dc.identifier.issn0066-4804
dc.identifier.urihttp://hdl.handle.net/10451/53190
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherASM Journalspt_PT
dc.relationINTERFERENCE OF MYCOBACTERIUM TUBERCULOSIS WITH THE ENDOCYTIC/ ANTIGEN PRESENTATION PATHWAYS ON MACROPHAGES AND DENDRITIC CELLS
dc.relationDissecting the intracelllular traffficking factors involved in M. tuberculosis killing/survival within human macrophages using RNA interference.
dc.relation.publisherversionhttps://journals.asm.org/journal/aacpt_PT
dc.titleThe mycobacterium tuberculosis outer membrane channel protein CpnT confers susceptibility to toxic moleculespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/63747/2009
oaire.awardNumberPIC/IC/82859/2007
oaire.awardNumberPTDC/BIA-BCM/102123/2008
oaire.awardNumberPTDC/SAU-MII/098024/2008
oaire.awardTitleINTERFERENCE OF MYCOBACTERIUM TUBERCULOSIS WITH THE ENDOCYTIC/ ANTIGEN PRESENTATION PATHWAYS ON MACROPHAGES AND DENDRITIC CELLS
oaire.awardTitleDissecting the intracelllular traffficking factors involved in M. tuberculosis killing/survival within human macrophages using RNA interference.
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F63747%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5646-ICCMS/PIC%2FIC%2F82859%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-BCM%2F102123%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-MII%2F098024%2F2008/PT
oaire.citation.endPage2336pt_PT
oaire.citation.issue4pt_PT
oaire.citation.startPage2328pt_PT
oaire.citation.titleAntimicrobial Agents and Chemotherapypt_PT
oaire.citation.volume59pt_PT
oaire.fundingStream5646-ICCMS
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
person.familyNameRODRIGUES PIRES
person.familyNameRIBEIRO DOS SANTOS ANES
person.givenNameDAVID ALEXANDRE
person.givenNameELSA MARIA
person.identifierD-8245-2012
person.identifierK-3124-2013
person.identifier.ciencia-id5816-D53E-F354
person.identifier.ciencia-id1A10-7DAD-D860
person.identifier.orcid0000-0001-9602-1516
person.identifier.orcid0000-0001-5934-0198
person.identifier.scopus-author-id50162243000
person.identifier.scopus-author-id6507064447
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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