A multi-targeting pre-clinical candidate against drug-resistant tuberculosis.

Autor: Kaur P; Foundation for Neglected Disease Research, Bangalore, India. Electronic address: parvinder.kaur@fndr.in., Potluri V; Foundation for Neglected Disease Research, Bangalore, India., Ahuja VK; Foundation for Neglected Disease Research, Bangalore, India., Naveenkumar CN; Foundation for Neglected Disease Research, Bangalore, India., Krishnamurthy RV; Foundation for Neglected Disease Research, Bangalore, India., Gangadharaiah ST; Anthem BioSciences. Pvt. Ltd., No 49, Canara Bank Road, Hosur Rd, Electronics City Phase 1, Bommasandra Industrial Area, Bengaluru, Karnataka, 560099, India., Shivarudraiah P; Anthem BioSciences. Pvt. Ltd., No 49, Canara Bank Road, Hosur Rd, Electronics City Phase 1, Bommasandra Industrial Area, Bengaluru, Karnataka, 560099, India., Eswaran S; Anthem BioSciences. Pvt. Ltd., No 49, Canara Bank Road, Hosur Rd, Electronics City Phase 1, Bommasandra Industrial Area, Bengaluru, Karnataka, 560099, India., Nirmal CR; National Institute for Research in Tuberculosis, No.1, Mayor Sathiyamoorthy St, Chetpet, Chennai, Tamil Nadu, 600031, India., Mahizhaveni B; National Institute for Research in Tuberculosis, No.1, Mayor Sathiyamoorthy St, Chetpet, Chennai, Tamil Nadu, 600031, India., Dusthackeer A; National Institute for Research in Tuberculosis, No.1, Mayor Sathiyamoorthy St, Chetpet, Chennai, Tamil Nadu, 600031, India., Mondal R; National Institute for Research in Tuberculosis, No.1, Mayor Sathiyamoorthy St, Chetpet, Chennai, Tamil Nadu, 600031, India., Batt SM; Insitiute of Microbiology & Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Richardson EJ; Insitiute of Microbiology & Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Loman NJ; Insitiute of Microbiology & Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Besra GS; Insitiute of Microbiology & Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Shandil RK; Foundation for Neglected Disease Research, Bangalore, India., Narayanan S; Foundation for Neglected Disease Research, Bangalore, India.
Jazyk: angličtina
Zdroj: Tuberculosis (Edinburgh, Scotland) [Tuberculosis (Edinb)] 2021 Jul; Vol. 129, pp. 102104. Date of Electronic Publication: 2021 Jun 18.
DOI: 10.1016/j.tube.2021.102104
Abstrakt: FNDR-20081 [4-{4-[5-(4-Isopropyl-phenyl)- [1,2,4]oxadiazol-3-ylmethyl]-piperazin-1-yl}-7-pyridin-3-yl-quinoline] is a novel, first in class anti-tubercular pre-clinical candidate against sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). In-vitro combination studies of FNDR-20081 with first- and second-line drugs exhibited no antagonism, suggesting its compatibility for developing new combination-regimens. FNDR-20081, which is non-toxic with no CYP3A4 liability, demonstrated exposure-dependent killing of replicating-Mtb, as well as the non-replicating-Mtb, and efficacy in a mouse model of infection. Whole genome sequencing (WGS) of FNDR-20081 resistant mutants revealed the identification of pleotropic targets: marR (Rv0678), a regulator of MmpL5, a transporter/efflux pump mechanism for drug resistance; and Rv3683, a putative metalloprotease potentially involved in peptidoglycan biosynthesis. In summary, FNDR-20081 is a promising first in class compound with the potential to form a new combination regimen for MDR-TB treatment.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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