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

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, Sarah M Batt, Emily J Richardson, Nicholas J Loman, Gurdyal Singh Besra, Radha Krishan Shandil, Shridhar Narayanan

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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.

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

Bibliographical note

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords

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

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