Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB

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Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB. / Abrahams, Katherine A; Cox, Jonathan A G; Spivey, Vickey L; Loman, Nicholas J; Pallen, Mark J; Constantinidou, Chrystala; Fernández, Raquel; Alemparte, Carlos; Remuiñán, Modesto J; Barros, David; Ballell, Lluis; Besra, Gurdyal S.

In: PLoS ONE, Vol. 7, No. 12, e52951, 2012.

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Abrahams, Katherine A ; Cox, Jonathan A G ; Spivey, Vickey L ; Loman, Nicholas J ; Pallen, Mark J ; Constantinidou, Chrystala ; Fernández, Raquel ; Alemparte, Carlos ; Remuiñán, Modesto J ; Barros, David ; Ballell, Lluis ; Besra, Gurdyal S. / Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB. In: PLoS ONE. 2012 ; Vol. 7, No. 12.

Bibtex

@article{bf572c87fcf043a4ac1f177bba545491,
title = "Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB",
abstract = "Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1-4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism (937)ACC>(937)GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.",
author = "Abrahams, {Katherine A} and Cox, {Jonathan A G} and Spivey, {Vickey L} and Loman, {Nicholas J} and Pallen, {Mark J} and Chrystala Constantinidou and Raquel Fern{\'a}ndez and Carlos Alemparte and Remui{\~n}{\'a}n, {Modesto J} and David Barros and Lluis Ballell and Besra, {Gurdyal S}",
year = "2012",
doi = "10.1371/journal.pone.0052951",
language = "English",
volume = "7",
journal = "PLoSONE",
issn = "1932-6203",
publisher = "Public Library of Science (PLOS)",
number = "12",

}

RIS

TY - JOUR

T1 - Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB

AU - Abrahams, Katherine A

AU - Cox, Jonathan A G

AU - Spivey, Vickey L

AU - Loman, Nicholas J

AU - Pallen, Mark J

AU - Constantinidou, Chrystala

AU - Fernández, Raquel

AU - Alemparte, Carlos

AU - Remuiñán, Modesto J

AU - Barros, David

AU - Ballell, Lluis

AU - Besra, Gurdyal S

PY - 2012

Y1 - 2012

N2 - Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1-4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism (937)ACC>(937)GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.

AB - Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1-4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism (937)ACC>(937)GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.

U2 - 10.1371/journal.pone.0052951

DO - 10.1371/journal.pone.0052951

M3 - Article

C2 - 23300833

VL - 7

JO - PLoSONE

JF - PLoSONE

SN - 1932-6203

IS - 12

M1 - e52951

ER -