Repository logo
 
Publication

Insights on the mechanism of action of INH-C-10 as an antitubercular prodrug

2017-12Journal article Restricted access
Simple item page
dc.contributor.authorVila-Viçosa, Diogo
dc.contributor.authorVictor, Bruno
dc.contributor.authorRamos, Jorge
dc.contributor.authorMachado, Diana
dc.contributor.authorViveiros, Miguel
dc.contributor.authorSwitala, Jacek
dc.contributor.authorLoewen, Peter C.
dc.contributor.authorElvas Leitao, Ruben
dc.contributor.authorMartins, Filomena
dc.contributor.authorMachuqueiro, Miguel
dc.date.accessioned2019-03-18T10:50:08Z
dc.date.available2019-03-18T10:50:08Z
dc.date.issued2017-12
dc.description.abstractTuberculosis remains one of the top causes of death worldwide, and combating its spread has been severely complicated by the emergence of drug-resistance mutations, highlighting the need for more effective drugs. Despite the resistance to isoniazid (INH) arising from mutations in the katG gene encoding the catalase-peroxidase KatG, most notably the S315T mutation, this compound is still one of the most powerful first-line antitubercular drugs, suggesting further pursuit of the development of tailored INH derivatives. The N'-acylated INH derivative with a long alkyl chain (INH-C-10) has been shown to be more effective than INH against the S315T variant of Mycobacterium tuberculosis, but the molecular details of this activity enhancement are still unknown. In this work, we show that INH N'-acylation significantly reduces the rate of production of both isonicotinoyl radical and isonicotinyl NAD by wild type KatG, but not by the S315T variant of KatG mirroring the in vivo effectiveness of the compound. Restrained and unrestrained MD simulations of INH and its derivatives at the water/membrane interface were performed and showed a higher preference of INH-C-10 for the lipidic phase combined with a significantly higher membrane permeability rate (27.9 cm s(-1), compared with INH-C-2 or INH (3.8 and 1.3 cm s-1, respectively). Thus, we propose that INH-C-10 is able to exhibit better minimum inhibitory concentration (MIC) values against certain variants because of its better ability to permeate through the lipid membrane, enhancing its availability inside the cell. MIC values of INH and INH-C-10 against two additional KatG mutations (S315N and D735A) revealed that some KatG variants are able to process INH faster than INH-C-10 into an effective antitubercular form (wt and S315N), while others show similar reaction rates (531ST and D735A). Altogether, our results highlight the potential of increased INH lipophilicity for treating INH-resistant strains.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationVILA-VIÇOSA, Diogo; [et al] – Insights on the mechanism of action of INH-C-10 as an antitubercular prodrug. Molecular Pharmaceutics. ISSN 1543-8384. Vol. 14, N.º 12 (2017), pp. 4597-4605pt_PT
dc.identifier.doi10.1021/acs.molpharmaceut.7b00719pt_PT
dc.identifier.issn1543-8384
dc.identifier.urihttp://hdl.handle.net/10400.21/9727
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Societypt_PT
dc.relationRGPIN9600 - Natural Sciences and Engineering Research Council (NSERC) of Canadapt_PT
dc.relationPTDC/QEQ-COM/5904/2014 - FCTpt_PT
dc.relationSFRH/BPD/100688/2014 - FCTpt_PT
dc.relationSFRH/BPD/110491/2015 - FCTpt_PT
dc.relation.publisherversionhttps://pubs.acs.org/doi/pdf/10.1021/acs.molpharmaceut.7b00719pt_PT
dc.subjectTuberculosispt_PT
dc.subjectKatGpt_PT
dc.subjectMutationpt_PT
dc.subjectActivationpt_PT
dc.subjectMembranept_PT
dc.subjectTuberculosept_PT
dc.subjectMutaçãopt_PT
dc.subjectAtivaçãopt_PT
dc.titleInsights on the mechanism of action of INH-C-10 as an antitubercular prodrugpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F00612%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04413%2F2013/PT
oaire.citation.endPage4605pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage4597pt_PT
oaire.citation.titleMolecular Pharmaceuticspt_PT
oaire.citation.volume14pt_PT
oaire.fundingStream5876
oaire.fundingStream5876
person.familyNameVila-Viçosa
person.familyNameVictor
person.familyNameRamos
person.familyNameMachado
person.familyNameViveiros Bettencourt
person.familyNameElvas Leitao
person.familyNamemartins
person.familyNameMachuqueiro
person.givenNameDiogo
person.givenNameBruno
person.givenNameJorge
person.givenNameDiana
person.givenNameMiguel
person.givenNameRuben
person.givenNamefilomena
person.givenNameMiguel
person.identifierA-7326-2008
person.identifier1433605
person.identifier.ciencia-id301B-7871-6E62
person.identifier.ciencia-id5A17-09B5-48A5
person.identifier.ciencia-id9E11-6132-9E26
person.identifier.ciencia-id731A-290A-31FC
person.identifier.ciencia-idDF17-B4BF-8756
person.identifier.ciencia-idF41B-8A26-88D4
person.identifier.ciencia-id7F12-A33A-EBAB
person.identifier.ciencia-idD416-CB5B-AC3D
person.identifier.orcid0000-0001-6620-0484
person.identifier.orcid0000-0002-6472-5700
person.identifier.orcid0000-0001-6419-5351
person.identifier.orcid0000-0003-2375-2726
person.identifier.orcid0000-0001-9676-6251
person.identifier.orcid0000-0002-2196-412X
person.identifier.orcid0000-0003-4189-1228
person.identifier.orcid0000-0001-6923-8744
person.identifier.ridA-2770-2012
person.identifier.ridL-2649-2016
person.identifier.ridD-2452-2009
person.identifier.ridE-6287-2012
person.identifier.ridC-8012-2011
person.identifier.scopus-author-id8791713500
person.identifier.scopus-author-id35307791000
person.identifier.scopus-author-id7003949212
person.identifier.scopus-author-id55667178200
person.identifier.scopus-author-id17342433200
person.identifier.scopus-author-id57221975472
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
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication95c18c60-fd29-40a6-b8ad-f5a6a5d65811
relation.isAuthorOfPublication331ff36d-5a01-45fe-a70f-52aaecf15554
relation.isAuthorOfPublicationb7f4ec69-c0f9-4ad5-a428-87d4fe28548d
relation.isAuthorOfPublication24dbe0f9-cd14-4c8d-b5cc-fbe3fc8a0bb2
relation.isAuthorOfPublication16d57ed3-3479-406d-b673-6912e073d086
relation.isAuthorOfPublication440b7129-d4d9-4225-a936-ca694c0984b6
relation.isAuthorOfPublicationa2fde0f8-54f8-445d-9015-315e0e4ba68b
relation.isAuthorOfPublication3466459e-d41d-436c-9b36-7e73e9d9cc9a
relation.isAuthorOfPublication.latestForDiscoveryb7f4ec69-c0f9-4ad5-a428-87d4fe28548d
relation.isProjectOfPublication718254be-c925-40e1-befc-ef8ab5913a8e
relation.isProjectOfPublication04d088f2-9131-4ec0-b664-4d5a1a703301
relation.isProjectOfPublication.latestForDiscovery718254be-c925-40e1-befc-ef8ab5913a8e

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
Insights_RLeitao.pdf
Size:
3.44 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

ISEL - Eng. Quim. Biol. - Artigos