Pyrrolo[3,4-<i>c</i>]pyridine-1,3(2<i>H</i>)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration

Westhuyzen, Renier van der; Winks, Susan; Wilson, Colin R.; Boyle, Grant A.; Gessner, Richard K.; Melo, Candice Soares de; Taylor, Dale; Kock, Carmen de; Njoroge, Mathew; Brunschwig, Christel; Lawrence, Nina; Rao, Srinivasa P. S.; Sirgel, Frederick A.; Helden, Paul van; Seldon, Ronnett; Moosa, A.; Warner, Digby F.; Arista, Luca; Manjunatha, Ujjini H.; Smith, Paul W.; Street, Leslie J.; Chibale, Kelly

doi:10.1021/acs.jmedchem.5b01542

Cited by 79 publications

(73 citation statements)

References 30 publications

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“…Hitherto, high-throughput screening efforts have mainly yielded classes of small-molecule inhibitors active on either ATP synthase (8, 26) or the cytochrome bc 1 complex (23, 25, 26). The reasons for this preference are obscure but may be related to the central role of these two enzymes in either establishing or utilizing the proton motive force.…”

Section: Introductionmentioning

confidence: 99%

“…Cytochrome bd is important for growth under low oxygen tensions as well as for survival in the mammalian host (34–36). Upon mutation or chemical inhibition of the cytochrome bc 1 complex, several M. tuberculosis strains are able reroute respiratory electron flux to cytochrome bd (24, 37, 38), leading to decreased sensitivity for cytochrome bc 1 inhibitors (24, 25). Cytochrome bd can also protect mycobacteria against bedaquiline (39–42) and clofazimine (41).…”

Section: Introductionmentioning

confidence: 99%

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Targeting Energy Metabolism in Mycobacterium tuberculosis , a New Paradigm in Antimycobacterial Drug Discovery

Bald

Villellas

Lü

et al. 2017

mBio

174

141

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Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy. The regulatory approval of the ATP synthase inhibitor bedaquiline and the discovery of Q203, a candidate drug targeting the cytochrome bc1 complex, have highlighted the central importance of this new target pathway. In this review, we discuss key features and potential applications of inhibiting energy metabolism in our quest for discovering potent novel and sterilizing drug combinations for combating tuberculosis. We believe that the combination of drugs targeting elements of the oxidative phosphorylation pathway can lead to a completely new regimen for drug-susceptible and multidrug-resistant tuberculosis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Energy Metabolism in Mycobacterium tuberculosis , a New Paradigm in Antimycobacterial Drug Discovery

Bald

Villellas

Lü

et al. 2017

mBio

174

141

View full text Add to dashboard Cite

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“…The first of these limitations can be ameliorated through the use of different screening conditions (6)(7)(8), whereas counterscreening strategies can eliminate known (and promiscuous) targets (9,10). In contrast, establishing the MOA usually depends on the ability to raise-and then genotype-mutant bacteria with heritable resistance to the applied agent (11).…”

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confidence: 99%

Bioluminescent Reporters for Rapid Mechanism of Action Assessment in Tuberculosis Drug Discovery

Naran

Moosa

Barry

et al. 2016

Antimicrob Agents Chemother

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cThe tuberculosis (TB) drug discovery pipeline is fueled by compounds identified in whole-cell screens against the causative agent, Mycobacterium tuberculosis. Phenotypic screening enables the selection of molecules that inhibit essential cellular functions in live, intact bacilli grown under a chosen in vitro condition. However, deducing the mechanism of action (MOA), which is important to avoid promiscuous targets, often requires significant biological resources in a lengthy process that risks decoupling medicinal chemistry and biology efforts. Therefore, there is a need to develop methods enabling rapid MOA assessment of putative "actives" for triage decisions. Here, we describe a modified version of a bioluminescence reporter assay that allows nondestructive detection of compounds targeting either of two macromolecular processes in M. tuberculosis: cell wall biosynthesis or maintenance of DNA integrity. Coupling the luxCDABE operon from Photorhabdus luminescens to mycobacterial promoters driving expression of the iniBAC operon (PiniB-LUX) or the DNA damage-inducible genes, recA (PrecA-LUX) or radA (PradA-LUX), provided quantitative detection in real time of compounds triggering expression of any of these promoters over an extended 10-to 12-day incubation. Testing against known anti-TB agents confirmed the specificity of each reporter in registering the MOA of the applied antibiotic in M. tuberculosis, independent of bactericidal or bacteriostatic activity. Moreover, profiles obtained for experimental compounds indicated the potential to infer complex MOAs in which multiple cellular processes are disrupted. These results demonstrate the utility of the reporters for early triage of compounds based on the provisional MOA and suggest their application to investigate polypharmacology in known and experimental anti-TB agents.

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“…The mycobacterial respiratory cytochrome bc1 complex was identified as the target for these compounds. Nevertheless, mouse pharmacokinetics studies showed high clearance and low plasma exposure for compound ( 28 ) [50]. In another study, a series of twenty-seven benzo[ d ]oxazol-2(3 H )-one derivatives were synthesized.…”

Section: Antituberculosis Compoundsmentioning

confidence: 99%

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

2017

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Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.

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Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration

Cited by 79 publications

References 30 publications

Targeting Energy Metabolism in Mycobacterium tuberculosis , a New Paradigm in Antimycobacterial Drug Discovery

Targeting Energy Metabolism in Mycobacterium tuberculosis , a New Paradigm in Antimycobacterial Drug Discovery

Bioluminescent Reporters for Rapid Mechanism of Action Assessment in Tuberculosis Drug Discovery

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

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