A Comprehensive Review on<i>Mycobacterium tuberculosis</i>Targets and Drug Development from a Structural Perspective

Pédelacq, J.D.; Nguyen, Minh; Terwilliger, Thomas C.; Mourey, Lionel

doi:10.1002/9781118681121.ch23

Cited by 9 publications

(12 citation statements)

References 177 publications

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“…This genotype is also reported to be strongly associated to multidrug resistance (MDR), mostly among human immunodeficiency virus (HIV) coinfected patients ( 35 , 36 ). Antibiotic resistance represents one of the main challenges in the treatment of TB and has become a major difficulty for the global control of the disease ( 37 , 38 ). Rifampin and isoniazid are first-line anti-TB agents.…”

Section: Discussionmentioning

confidence: 99%

“…Rifampin and isoniazid are first-line anti-TB agents. Relevant mutations in the beta subunit of the RNA polymerase ( rpoB ) gene and mutations in the catalase-peroxidase enzyme gene ( katG ) can be involved in RMP and INH resistance to M. tuberculosis , respectively ( 37 ). Nevertheless, in the present study, we observed no mutation on the rpoB and katG genes of our SIT42 isolate, suggesting susceptibility to both rifampin and isoniazid relative antibiotics.…”

Section: Discussionmentioning

confidence: 99%

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Mycobacterium tuberculosis SIT42 Infection in an Abused Dog in Southern Italy

et al. 2021

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A case of Mycobacterium tuberculosis infection is described in a dead adult male dog in Southern Italy. The carcass was found by the Health Authority in a gypsy encampment. It was admitted to our forensic veterinary medicine unit, with a suspicion of cruelty to the animal. Necropsy showed beating and traumatism signs, and mistreating was confirmed. Gross lesions included multiple nodular hepatic lesions, hemorrhagic enteritis with enlarged mesenteric lymph nodes, body cavity effusions, and an adrenal neoplasm. Bacteriological and molecular analyses were carried out on the liver lesions that enabled to identify M. tuberculosis SIT42 (LAM9). Drug-resistance patterns were evaluated by screening mutations on the rpoB and katG genes that showed susceptibility to both rifampin and isoniazid, respectively. Very few studies report canine tuberculosis, and little is known about the disease in Italy. To the authors' knowledge, this is the first report of Mycobacterium tuberculosis SIT42 infection in a dog in Italy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis SIT42 Infection in an Abused Dog in Southern Italy

et al. 2021

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“…The rise of drug-resistant tuberculosis (TB) in recent times has become a major global health problem [ 1 ], and this resurgence of such a major infectious disease has also provided an impetus for the development of new classes of drugs. These are aimed at a wide variety of mycobacterial targets, including the control of gene expression [ 2 ], inhibition of drug efflux pumps [ 3 ], and of proteins in the mycobacterial electron transport chain [ 4 ]. In particular, the spectacular success of the drug bedaquiline in treating multi-drug-resistant TB (MDR-TB) by inhibition of the mycobacterial enzyme ATP synthase has resulted in a largely curative regime (NIX-TB) [ 5 ] for this disease, despite bedaquiline's side effect of hERG channel inhibition.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis

Sutherland

Tong

Conole

et al. 2022

European Journal of Medicinal Chemistry

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Drug resistant tuberculsosis (TB) is global health crisis that demands novel treatment strategies. Bacterial ATP synthase inhibitors such as bedaquiline and next-generation analogues (such as TBAJ-876) have shown promising efficacy in patient populations and preclinical studies, respectively, suggesting that selective targeting of this enzyme presents a validated therapeutic strategy for the treatment of TB. In this work, we report tetrahydronaphthalene amides (THNAs) as a new class of ATP synthase inhibitors that are effective in preventing the growth of Mycobacterium tuberculosis (M.tb) in culture. Design, synthesis and comprehensive structure-activity relationship studies for approximately 80 THNA analogues are described, with a small selection of compounds exhibiting potent (in some cases MIC 90 <1 μg/mL) in vitro M.tb growth inhibition taken forward to pharmacokinetic and off-target profiling studies. Ultimately, we show that some of these THNAs possess reduced lipophilic properties, decreased hERG liability, faster mouse/human liver microsomal clearance rates and shorter plasma half-lives compared with bedaquiline, potentially addressing of the main concerns of persistence and phospholipidosis associated with bedaquiline.

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“…The purpose of this review was not to provide an exhaustive overview of the capabilities now offered by in silico approaches for antibiotic development against M. tuberculosis, already reviewed elsewhere [26,27], nor to make a survey of the current state of structural knowledge of the pathogen proteome and the experimental structures relevant for drug discovery, for which we point the reader to very recent, extensive work [28]. Rather, we focused here on three emblematic case studies of M. tuberculosis targets that attracted most efforts for anti-tuberculosis compound development by HTS campaigns, computer-aided, and structure-driven compound identification: the serine/threonine (Ser/Thr) kinases-protein kinase (Pkn)B and PknG-two amongst the most known, supposedly promising new targets offered by the post-genomic era, and the DNA gyrase, the 'old' but the well-proven target of fluoroquinolones.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Drug Design for Tuberculosis: Challenges Still Ahead

2020

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Structure-based and computer-aided drug design approaches are commonly considered to have been successful in the fields of cancer and antiviral drug discovery but not as much for antibacterial drug development. The search for novel anti-tuberculosis agents is indeed an emblematic example of this trend. Although huge efforts, by consortiums and groups worldwide, dramatically increased the structural coverage of the Mycobacterium tuberculosis proteome, the vast majority of candidate drugs included in clinical trials during the last decade were issued from phenotypic screenings on whole mycobacterial cells. We developed here three selected case studies, i.e., the serine/threonine (Ser/Thr) kinases—protein kinase (Pkn) B and PknG, considered as very promising targets for a long time, and the DNA gyrase of M. tuberculosis, a well-known, pharmacologically validated target. We illustrated some of the challenges that rational, target-based drug discovery programs in tuberculosis (TB) still have to face, and, finally, discussed the perspectives opened by the recent, methodological developments in structural biology and integrative techniques.

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A Comprehensive Review onMycobacterium tuberculosisTargets and Drug Development from a Structural Perspective

Cited by 9 publications

References 177 publications

Mycobacterium tuberculosis SIT42 Infection in an Abused Dog in Southern Italy

Mycobacterium tuberculosis SIT42 Infection in an Abused Dog in Southern Italy

Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis

Structure-Based Drug Design for Tuberculosis: Challenges Still Ahead

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