Contribution of direct InhA inhibitors to novel drug regimens in a mouse model of tuberculosis

Encinas, Lourdes (author), Li, Si-Yang (author), Rullas-Trincado, Joaquin (author), Tasneen, Rokeya (author), Tyagi, Sandeep (author), Soni, Heena (author), Garcia-Perez, Adolfo (author), Lee, Jin (author), Sosič, Izidor (author), Gobec, Stanislav (author)

Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving katG, encoding the prodrug-activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs). In this study, we bridge the gap in understanding the potential contribution of DIIs to novel combination regimens and demonstrate a clear distinction of DIIs, like GSK693 and the newly described GSK138, from isoniazid, based on activity against clinical isolates and contribution to novel drug regimens. The results suggest that DIIs, specifically GSK138 and GSK693, could be promising partners in novel drug regimens, including those used against isoniazid-resistant TB, potentially enhancing their efficacy and/or preventing the selection of resistant mutants and supporting the continued exploration of InhA as a promising target for TB drug development.

• Language: English
• Keywords: InhA inhibitor, tuberculosis, mouse, GSK138, GSK3081138A, GSK693, GSK2505693A, tuberculosis drugs
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 17 str.
• Numbering: Vol. 68, iss. 11
• PID: 20.500.12556/RUL-165224
• UDC: 615.2:616-002.5
• ISSN on article: 1098-6596
• DOI: 10.1128/aac.00357-24
• COBISS.SI-ID: 209594883
• Publication date in RUL: 27.11.2024

Record is a part of a journal

• Title: Antimicrobial agents and chemotherapy
• Shortened title: Antimicrob Agents Chemother
• Publisher: American Society for Microbiology
• ISSN: 1098-6596
• COBISS.SI-ID: 3070228

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: zaviralec InhA, miš, GSK138, GSK3081138A, GSK693, GSK2505693A, zdravila za tuberkulozom tuberkuloza, zdravila

Projects

• Funder: EC - European Commission
• Funding programme: FP7/2007-2013
• Project number: 261378
• Name: Open Collaborative Model for Tuberculosis Lead Optimisation
• Acronym: ORCHID