Challenges in tuberculosis drug research and development

Ginsberg, Ann M.; Spigelman, Melvin

doi:10.1038/nm0307-290

Cited by 244 publications

(187 citation statements)

References 17 publications

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“…A formidable obstacle to successful treatment of TB is the requirement for frequent administration of multiple drugs for 6 mo or longer (2). Unless drug administration is closely supervised, the majority of patients will not adhere to such a protracted therapeutical regimen (2). Consequently, patient nonadherence is responsible for high rates of treatment failure, relapse, and emergent drug resistance (3).…”

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confidence: 99%

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Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice

Dhar

McKinney

2010

Proc. Natl. Acad. Sci. U.S.A.

114

106

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Tuberculosis (TB) is notoriously difficult to cure, requiring administration of multiple antibiotics for 6 mo or longer. Conventional anti-TB drugs inhibit biosynthetic processes involved in cell growth and division, such as DNA replication, RNA transcription, protein translation, and cell wall biogenesis. Although highly effective against bacteria cultured in vitro under optimal growth conditions, these antibiotics are less effective against bacteria grown in vivo in the tissues of a mammalian host. The factors that contribute to the antibiotic tolerance of bacteria grown in vivo are unknown, although altered metabolism and sluggish growth are hypothesized to play a role. To address this question, we identified mutations in Mycobacterium tuberculosis that impaired or enhanced persistence in mice treated with isoniazid (INH), a front-line anti-TB drug. Disruption of cydC, encoding a putative ATP-binding cassette transporter subunit, accelerated bacterial clearance in INH-treated mice without affecting growth or survival in untreated mice. Conversely, transposon insertions within the rv0096-rv0101 gene cluster attenuated bacterial growth and survival in untreated mice but paradoxically prevented INH-mediated killing of bacteria in treated mice. These contrasting phenotypes were dependent on the interaction of the bacteria with the tissue environment because both mutants responded normally to INH when grown in macrophages ex vivo or in axenic cultures in vitro. Our findings have important implications because persistence-impairing mutations would be missed by conventional genetic screens to identify candidate drug targets. Conversely, persistenceenhancing mutations would be missed by standard diagnostic methods, which are performed on bacteria grown in vitro, to detect drug resistance.chemotherapy | drug tolerance | host environment T uberculosis (TB) has been a treatable disease for more than half a century, yet TB eradication remains a distant and possibly unachievable goal barring the introduction of more effective control strategies (1). A formidable obstacle to successful treatment of TB is the requirement for frequent administration of multiple drugs for 6 mo or longer (2). Unless drug administration is closely supervised, the majority of patients will not adhere to such a protracted therapeutical regimen (2). Consequently, patient nonadherence is responsible for high rates of treatment failure, relapse, and emergent drug resistance (3). To reduce treatment costs and improve patient adherence, there is an urgent need for more effective anti-TB drugs to shorten the treatment time (2, 4).Conventional anti-TB drugs target biosynthetic processes involved in cell growth, including RNA transcription [rifampicin (RIF)], protein translation (streptomycin), and cell wall biogenesis [isoniazid (INH)]. Although these drugs rapidly kill Mycobacterium tuberculosis grown in vitro, they are less active against bacteria grown in vivo in mammalian hosts (4,5). In the mouse model of TB, infection progresses through a brief ac...

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confidence: 99%

“…Consequently, patient nonadherence is responsible for high rates of treatment failure, relapse, and emergent drug resistance (3). To reduce treatment costs and improve patient adherence, there is an urgent need for more effective anti-TB drugs to shorten the treatment time (2,4).…”

mentioning

confidence: 99%

Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice

Dhar

McKinney

2010

Proc. Natl. Acad. Sci. U.S.A.

114

106

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“…The rationale for testing different doses, regimens, and sequence of add-on drugs of each potential combination is clearly inefficient [8]. At least 6 years (an estimated 1 year for Phase I, 2 years for Phase II, and 3 years for Phase III) are required to develop one new antibiotic [1], whereas more than two decades (46 years) would be needed for the development and approval of a completely novel regimen comprising four new antibiotics through successive trials [1]. Here, we focus on how an integrated PKPD-disease modelling and simulation framework, also known as model-informed drug discovery and development (MID3), could accelerate the development of novel combination therapies and highlight the potential impact of such framework to inform more robust decision making in TB drug development.…”

Section: Shift In the Tb Drug Development Paradigm: Reality Or Fiction?mentioning

confidence: 99%

“…The development of new combination therapies for TB is lengthy and costly [1]. Despite promising advances in the field, innovative methods are still needed to effectively transition the growing number of compounds into novel combination regimens.…”

Section: Introductionmentioning

confidence: 99%

The implications of model-informed drug discovery and development for tuberculosis

Muliaditan¹,

Davies

Simonsson

et al. 2017

Drug Discovery Today

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“…When coupled with the emergence of multidrug-resistant strains of M. tuberculosis (MDR-TB)/the scale of the problem becomes clear, as it will inevitably become even more difficult to treat TB [3]. This has spurred new efforts to find new anti-tuberculosis drug candidates with novel modes of action, develop pipelines for drug discovery and try to find new regimens that can considerably shorten the duration of effective therapy which would improve patient compliance and slow down the emergence of drug resistant strains [4][5][6][7][8][9]. Benzofuran is widespread interest in the field of synthetic chemistry and natural products has attracted due to their biological activities and their potential applications as pharmacological agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antimicrobial, Antitubercular and Cheminformatic Studies of 2-(1-Benzofuran-2-Yl)-N'-[(3z)-2-Oxo-1, 2-Dihydro-3h-Indol-3-Ylidene] Quinoline-4-Carbohydrazide and Its Derivatives

Santoshkumar

Satyanarayana

Anantacharya

et al. 2017

Int J Pharm Pharm Sci

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Objective: Synthesis of novel 2-(1-benzofuran-2-yl)-N'-[(3Z)-2-oxo-1, 2-dihydro-3H-indol-3-ylidene] quinoline-4-carbohydrazide and its derivatives for antimicrobial and antitubercular activity.Methods: Synthesis was carried out using the general method and the structures were confirmed by IR, 1 Results:The results revealed that at 25 mg/ml concentration, compounds 3a and 5a showed good antibacterial activity at 3.5±0.1, 3.8±0.3, 3.6±0.2 respectively against E. coli, K. pneumonia and S. typhimurium, when compared with drug streptomycin with similar concentration. The percentage of inhibition found at 50 µg/ml concentration, compounds 2b and 6a exhibited good antifungal activity at 53±1.15, 57±1.52 against A. flavus and C. neoformans, compared with standard drug fluconazole. The increase in activity was found to be dose dependent. The analogue 2a showed good antitubercular activity at 12.5±0.5 µg/ml, compounds 2b, 3a, 4a-b, 5a-b and 6a-b exhibited significant activity at 25±0.57 µg/ml and compound 3b showed moderate activity at 50±0.57 µg/ml. The mean value of P<0.05 were considered to be statistically significant. The absorption, distribution, metabolism, excretion and toxicity studies of the entitled molecules were analyzed and found to be in acceptable range.H-NMR, [13]C-NMR and mass spectral analysis. The antibacterial activity was carried by agar well diffusion method, antifungal activity was performed by poison food technique and antitubercular activity was carried out by Microplate Alamar Blue Assay (MABA) method with the help of H37Rv. In silico absorption, distribution, metabolism, excretion, toxicity (ADMET) study of the drug, likeliness was carried out in ACD/lab-2. Conclusion:The study reveals that compounds containing benzofuran coupled nitrogen heterocycles are essential for activity as they possess excellent drug-like characteristics, suggesting to be potentially best inhibitor of H37Rv strain. The in silico ADME analysis also revealed that all the compounds were in acceptable range to obey the pharmacokinetic parameters.

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Challenges in tuberculosis drug research and development

Cited by 244 publications

References 17 publications

Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice

Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice

The implications of model-informed drug discovery and development for tuberculosis

Synthesis, Antimicrobial, Antitubercular and Cheminformatic Studies of 2-(1-Benzofuran-2-Yl)-N'-[(3z)-2-Oxo-1, 2-Dihydro-3h-Indol-3-Ylidene] Quinoline-4-Carbohydrazide and Its Derivatives

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