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

Research output: Contribution to journalArticlepeer-review

Authors

  • Parvinder Kaur
  • Vijay Potluri
  • Vijay Kamal Ahuja
  • C N Naveenkumar
  • Ramya Vadageri Krishnamurthy
  • Shruthi Thimmalapura Gangadharaiah
  • Prasad Shivarudraiah
  • Sumesh Eswaran
  • Christy Rosaline Nirmal
  • Balasubramanian Mahizhaveni
  • Azger Dusthackeer
  • Rajesh Mondal
  • Nicholas J Loman
  • Radha Krishan Shandil
  • Shridhar Narayanan

External organisations

  • Foundation for Neglected Disease Research
  • Anthem BioSciences. Pvt. Ltd.
  • National Institute for Research in Tuberculosis

Abstract

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.

Bibliographic note

Copyright © 2021 Elsevier Ltd. All rights reserved.

Details

Original languageEnglish
Article number102104
Number of pages11
JournalTuberculosis
Volume129
Early online date18 Jun 2021
Publication statusPublished - Jul 2021

Keywords

  • Drug resistance, Mycobacterium tuberculosis, First-in-class, Multi-target, Pre-clinical candidate

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