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Publication details

Document type
Journal articles

Document subtype
Full paper

Title
Insights on the Mechanism of Action of INH-C10 as an Antitubercular Prodrug

Participants in the publication
Diogo Vila-Viçosa (Author)
Dep. Química e Bioquímica
CQB - Centro de Química e Bioquímica 
Bruno L. Victor (Author)
Dep. Química e Bioquímica
CQB - Centro de Química e Bioquímica 
Jorge Ramos (Author)
Diana Machado (Author)
Miguel Viveiros (Author)
Jacek Switala (Author)
Peter C. Loewen (Author)
Ruben Leitão (Author)
Filomena Martins (Author)
Dep. Química e Bioquímica
CQB - Centro de Química e Bioquímica 
Miguel Machuqueiro (Author)
Dep. Química e Bioquímica
CQB - Centro de Química e Bioquímica 

Scope
International

Refereeing
Yes

Summary
Tuberculosis 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-C10) 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-C10 for the lipidic phase combined with a significantly higher membrane permeability rate (27.9 cm s–1), compared with INH-C2 or INH (3.8 and 1.3 cm s–1, respectively). Thus, we propose that INH-C10 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-C10 against two additional KatG mutations (S315N and D735A) revealed that some KatG variants are able to process INH faster than INH-C10 into an effective antitubercular form (wt and S315N), while others show similar reaction rates (S315T and D735A). Altogether, our results highlight the potential of increased INH lipophilicity for treating INH-resistant strains.

Date of Submisson/Request
2017-08-21
Date of Acceptance
2017-11-01
Date of Publication
2017-11-01

Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Where published
Molecular Pharmaceutics

Publication Identifiers
ISSN - 1543-8384

Publisher
American Chemical Society (ACS)

Volume
14
Number
12

Number of pages
8
Starting page
4597
Last page
4605

Document Identifiers
URL - http://dx.doi.org/10.1021/acs.molpharmaceut.7b00719
DOI - https://doi.org/10.1021/acs.molpharmaceut.7b00719

Rankings
Web Of Science Q1 (2017) - 4.556 - PHARMACOLOGY & PHARMACY - SCIE
SCOPUS Q1 (2017) - 1.572 - Pharmaceutical Science
SCOPUS Q1 (2017) - 1.572 - Drug Discovery
SCIMAGO Q1 (2017) - 1.572 - Pharmaceutical Science
SCIMAGO Q1 (2017) - 1.572 - Drug Discovery

Keywords
mutation KatG tuberculosis activation membrane


Export

APA
Diogo Vila-Viçosa, Bruno L. Victor, Jorge Ramos, Diana Machado, Miguel Viveiros, Jacek Switala, Peter C. Loewen, Ruben Leitão, Filomena Martins, Miguel Machuqueiro, (2017). Insights on the Mechanism of Action of INH-C10 as an Antitubercular Prodrug. Molecular Pharmaceutics, 14, 4597-4605. ISSN 1543-8384. eISSN . http://dx.doi.org/10.1021/acs.molpharmaceut.7b00719

IEEE
Diogo Vila-Viçosa, Bruno L. Victor, Jorge Ramos, Diana Machado, Miguel Viveiros, Jacek Switala, Peter C. Loewen, Ruben Leitão, Filomena Martins, Miguel Machuqueiro, "Insights on the Mechanism of Action of INH-C10 as an Antitubercular Prodrug" in Molecular Pharmaceutics, vol. 14, pp. 4597-4605, 2017. 10.1021/acs.molpharmaceut.7b00719

BIBTEX
@article{36049, author = {Diogo Vila-Viçosa and Bruno L. Victor and Jorge Ramos and Diana Machado and Miguel Viveiros and Jacek Switala and Peter C. Loewen and Ruben Leitão and Filomena Martins and Miguel Machuqueiro}, title = {Insights on the Mechanism of Action of INH-C10 as an Antitubercular Prodrug}, journal = {Molecular Pharmaceutics}, year = 2017, pages = {4597-4605}, volume = 14 }