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

Abrahams, Katherine A.; Cox, Jonathan; Spivey, Vickey L.; Loman, Nicholas J.; Pallen, Mark J.; Constantinidou, Chrystala; Fernández, Raquel M.; Alemparte, Carlos; Remuiñán, Modesto J.; Barros, David; Ballell, Lluís; Besra, Gurdyal S.

doi:10.1371/journal.pone.0052951

Cited by 166 publications

(186 citation statements)

References 51 publications

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“…More recent efforts have yielded a novel class of imidazo[1,2-a]pyridine amide (IPA) compounds (77,78) that prevent proliferation of M. tuberculosis by inhibition of the cytochrome bc 1 reductase complex in the mycobacterial respiratory chain (77, 79) (Fig. 1).…”

Section: Drugs That Target the Etcmentioning

confidence: 99%

“…These compounds bind the QcrB subunit and induce bacterial cell death by abrogating electron flow through the ETC, resulting in reduced ATP synthesis under aerobic and anaerobic conditions (79). Two independent studies identified QcrB as the target for IPAs through the generation of spontaneous resistant mutants carrying various substitutions at the Thr313 residue (77,79). The lead compound from this series, Q203, displays potent killing of M. tuberculosis in axenic culture, in macrophages, and in the murine model of TB infection, with a spontaneous mutation rate in the order of 10 Ϫ8 (79).…”

Section: Drugs That Target the Etcmentioning

confidence: 99%

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Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Black

Warren

Louw

et al. 2014

Antimicrob Agents Chemother

117

102

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cThe inherent drug susceptibility of microorganisms is determined by multiple factors, including growth state, the rate of drug diffusion into and out of the cell, and the intrinsic vulnerability of drug targets with regard to the corresponding antimicrobial agent. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a significant source of global morbidity and mortality, further exacerbated by its ability to readily evolve drug resistance. It is well accepted that drug resistance in M. tuberculosis is driven by the acquisition of chromosomal mutations in genes encoding drug targets/promoter regions; however, a comprehensive description of the molecular mechanisms that fuel drug resistance in the clinical setting is currently lacking. In this context, there is a growing body of evidence suggesting that active extrusion of drugs from the cell is critical for drug tolerance. M. tuberculosis encodes representatives of a diverse range of multidrug transporters, many of which are dependent on the proton motive force (PMF) or the availability of ATP. This suggests that energy metabolism and ATP production through the PMF, which is established by the electron transport chain (ETC), are critical in determining the drug susceptibility of M. tuberculosis. In this review, we detail advances in the study of the mycobacterial ETC and highlight drugs that target various components of the ETC. We provide an overview of some of the efflux pumps present in M. tuberculosis and their association, if any, with drug transport and concomitant effects on drug resistance. The implications of inhibiting drug extrusion, through the use of efflux pump inhibitors, are also discussed.

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Section: Drugs That Target the Etcmentioning

confidence: 99%

Section: Drugs That Target the Etcmentioning

confidence: 99%

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Black

Warren

Louw

et al. 2014

Antimicrob Agents Chemother

117

102

View full text Add to dashboard Cite

show abstract

“…23 The hit compounds 34 and 35 showed potent anti TB activity with no evident signs of cytotoxicity (CC 50 25 μM for 4 different cell lines, CC 50 : 50% cytotoxicity concentration), however these compounds suffered from low stability in mouse microsomal fractions. Their medicinal chemistry efforts were pursued to improve the metabolic stability issue, resulting in the identi cation of 36 and 37.…”

Section: Imidazopyridine Amides (Ipa)mentioning

confidence: 96%

Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

Yokokawa

2014

J. Synth. Org. Chem. Jpn.

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) continues to be a serious major global health risk. More than one third of the world s human population is infected, resulting in 1.4 2.0 million deaths per year. The rst line therapy using a multidrug regimen has existed since the 1970s, however, there has been an alarming increase in the number of patients with multi (MDR) and extensive (XDR) drug resistant TB in recent years. Hence, there is an urgent need to develop novel drugs with new mechanisms of action and new chemotypes in order to combat drug resistant TB. A target based approach to nding new anti TB agents has been widely used, however this approach has not led to the identi cation of clinical candidates. The recent trend has been to go back to whole cell screens, in which compounds are identi ed based on their anti TB activity. Consequently, various groups have reported structurally diverse active compounds against Mtb, which were originally identi ed from phenotypic screens. This review will cover recent scienti c accounts published from these groups that have described medicinal chemistry optimization studies from whole cell screening hits. In vivo pharmacokinetics and ef cacy of optimized compounds as well as their potential molecular targets will be also discussed.

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“…76 A inibição da subunidade b do citocromo (QcrB) bc1-aa3 foi identificada como alvo para derivados imidazol[1,2-α]piridina (24) (Figura 9). 77 O complexo citocromo bc1 apresenta um papel crucial para a cadeia transportadora de elétrons durante a síntese de ATP e, consequentemente, para o crescimento da micobacteria. 78 No entanto, já foi relatado que durante o crescimento aeróbio do MTB, a participação do citocromo bd oxidase pode compensar os efeitos inibitórios do complexo citocromo bc1.…”

Section: Alvos Envolvidos Com a Geração De Energiaunclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

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

Cited by 166 publications

References 51 publications

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

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