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

doi:10.1016/j.tube.2021.102104

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 language	English
Article number	102104
Number of pages	11
Journal	Tuberculosis
Volume	129
Early online date	18 Jun 2021
DOIs	https://doi.org/10.1016/j.tube.2021.102104
Publication status	Published - Jul 2021

Bibliographical note

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kaur, P., Potluri, V., Ahuja, V. K., Naveenkumar, C. N., Krishnamurthy, R. V., Gangadharaiah, S. T., Shivarudraiah, P., Eswaran, S., Nirmal, C. R., Mahizhaveni, B., Dusthackeer, A., Mondal, R., Batt, S. M., Richardson, E. J., Loman, N. J., Besra, G. S., Shandil, R. K., & Narayanan, S. (2021). A multi-targeting pre-clinical candidate against drug-resistant tuberculosis. Tuberculosis, 129, Article 102104. Advance online publication. https://doi.org/10.1016/j.tube.2021.102104

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title = "A multi-targeting pre-clinical candidate against drug-resistant 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.",

keywords = "Drug resistance, First-in-class, Multi-target, Mycobacterium tuberculosis, Pre-clinical candidate",

author = "Parvinder Kaur and Vijay Potluri and Ahuja, {Vijay Kamal} and Naveenkumar, {C N} and Krishnamurthy, {Ramya Vadageri} and Gangadharaiah, {Shruthi Thimmalapura} and Prasad Shivarudraiah and Sumesh Eswaran and Nirmal, {Christy Rosaline} and Balasubramanian Mahizhaveni and Azger Dusthackeer and Rajesh Mondal and Batt, {Sarah M} and Richardson, {Emily J} and Loman, {Nicholas J} and Besra, {Gurdyal Singh} and Shandil, {Radha Krishan} and Shridhar Narayanan",

year = "2021",

month = jul,

doi = "10.1016/j.tube.2021.102104",

language = "English",

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journal = "Tuberculosis",

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Kaur, P, Potluri, V, Ahuja, VK, Naveenkumar, CN, Krishnamurthy, RV, Gangadharaiah, ST, Shivarudraiah, P, Eswaran, S, Nirmal, CR, Mahizhaveni, B, Dusthackeer, A, Mondal, R, Batt, SM, Richardson, EJ, Loman, NJ, Besra, GS, Shandil, RK & Narayanan, S 2021, 'A multi-targeting pre-clinical candidate against drug-resistant tuberculosis', Tuberculosis, vol. 129, 102104. https://doi.org/10.1016/j.tube.2021.102104

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AU - Kaur, Parvinder

AU - Potluri, Vijay

AU - Ahuja, Vijay Kamal

AU - Naveenkumar, C N

AU - Krishnamurthy, Ramya Vadageri

AU - Gangadharaiah, Shruthi Thimmalapura

AU - Shivarudraiah, Prasad

AU - Eswaran, Sumesh

AU - Nirmal, Christy Rosaline

AU - Mahizhaveni, Balasubramanian

AU - Dusthackeer, Azger

AU - Mondal, Rajesh

AU - Batt, Sarah M

AU - Richardson, Emily J

AU - Loman, Nicholas J

AU - Besra, Gurdyal Singh

AU - Shandil, Radha Krishan

AU - Narayanan, Shridhar

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

KW - Drug resistance

KW - First-in-class

KW - Multi-target

KW - Mycobacterium tuberculosis

KW - Pre-clinical candidate

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U2 - 10.1016/j.tube.2021.102104

DO - 10.1016/j.tube.2021.102104

M3 - Article

C2 - 34214859

SN - 1472-9792

VL - 129

JO - Tuberculosis

JF - Tuberculosis

M1 - 102104

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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