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Article ; Online: Two Decades of TB Drug Discovery Efforts—What Have We Learned?

Balachandra Bandodkar / Radha Krishan Shandil / Jagadeesh Bhat / Tanjore S. Balganesh

Applied Sciences, Vol 10, Iss 5704, p

2020 Volume 5704

Abstract: After several years of limited success, an effective regimen for the treatment of both drug-sensitive and multiple-drug-resistant tuberculosis is in place. However, this success is still incomplete, as we need several more novel combinations to treat ... ...

Abstract	After several years of limited success, an effective regimen for the treatment of both drug-sensitive and multiple-drug-resistant tuberculosis is in place. However, this success is still incomplete, as we need several more novel combinations to treat extensively drug-resistant tuberculosis, as well newer emerging resistance. Additionally, the goal of a shortened therapy continues to evade us. A systematic analysis of the tuberculosis drug discovery approaches employed over the last two decades shows that the lead identification path has been largely influenced by the improved understanding of the biology of the pathogen Mycobacterium tuberculosis . Interestingly, the drug discovery efforts can be grouped into a few defined approaches that predominated over a period of time. This review delineates the key drivers during each of these periods. While doing so, the author’s experiences at AstraZeneca R&D, Bangalore, India, on the discovery of new antimycobacterial candidate drugs are used to exemplify the concept. Finally, the review also discusses the value of validated targets, promiscuous targets, the current anti-TB pipeline, the gaps in it, and the possible way forward.
Keywords	tuberculosis ; Mycobacterium tuberculosis ; drug discovery ; drug development ; target-based screening ; phenotypic screening ; Technology ; T ; Engineering (General). Civil engineering (General) ; TA1-2040 ; Biology (General) ; QH301-705.5 ; Physics ; QC1-999 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Exploring the potential of adjunct therapy in tuberculosis.

Rayasam, Geetha Vani / Balganesh, Tanjore S

Trends in pharmacological sciences

2015 Volume 36, Issue 8, Page(s) 506–513

Abstract: A critical unmet need for treatment of drug-resistant tuberculosis (TB) is to find novel therapies that are efficacious, safe, and shorten the duration of treatment. Drug discovery approaches for TB primarily target essential genes of the pathogen ... ...

Abstract	A critical unmet need for treatment of drug-resistant tuberculosis (TB) is to find novel therapies that are efficacious, safe, and shorten the duration of treatment. Drug discovery approaches for TB primarily target essential genes of the pathogen Mycobacterium tuberculosis (Mtb) but novel strategies such as host-directed therapies and nonmicrobicidal targets are necessary to bring about a paradigm shift in treatment. Drugs targeting the host pathways and nonmicrobicidal proteins can be used only in conjunction with existing drugs as adjunct therapies. Significantly, host-directed adjunct therapies have the potential to decrease duration of treatment, as they are less prone to drug resistance, target the immune responses, and act via novel mechanism of action. Recent advances in targeting host-pathogen interactions have implicated pathways such as eicosanoid regulation and angiogenesis. Furthermore, several approved drugs such as metformin and verapamil have been identified that appear suitable for repurposing for the treatment of TB. These findings and the challenges in the area of host- and/or pathogen-directed adjunct therapies and their implications for TB therapy are discussed.
MeSH term(s)	Animals ; Chemotherapy, Adjuvant ; Clinical Trials as Topic ; Host-Pathogen Interactions ; Humans ; Tuberculosis, Multidrug-Resistant/drug therapy
Language	English
Publishing date	2015-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2015.05.005
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Article: Drug discovery research in India: current state and future prospects.

Balganesh, Tanjore / Kundu, Tapas K / Chakraborty, Tushar Kanti / Roy, Siddhartha

ACS medicinal chemistry letters

2014 Volume 5, Issue 7, Page(s) 724–726

Abstract: Indian civilization developed a strong system of traditional medicine and was one of the first nations to develop a synthetic drug. In the postindependence era, Indian pharmaceutical industry developed a strong base for production of generic drugs. ... ...

Abstract	Indian civilization developed a strong system of traditional medicine and was one of the first nations to develop a synthetic drug. In the postindependence era, Indian pharmaceutical industry developed a strong base for production of generic drugs. Challenges for the future are to give its traditional medicine a strong scientific base and develop research and clinical capability to consistently produce new drugs based on advances in modern biological sciences.
Language	English
Publishing date	2014-05-23
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/ml500183c
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Article ; Online: Biomedicine and Biotechnology

Nirmal K. Ganguly / Simon Croft / Lalji Singh / Subrata Sinha / Tanjore Balganesh

BioMed Research International, Vol

Public Health Impact

2014 Volume 2014

Keywords	Medicine ; R
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
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Article ; Online: Biomedicine and biotechnology: public health impact.

Ganguly, Nirmal K / Croft, Simon / Singh, Lalji / Sinha, Subrata / Balganesh, Tanjore

BioMed research international

2014 Volume 2014, Page(s) 524785

MeSH term(s)	Animals ; Anti-Infective Agents/pharmacology ; Biomedical Research ; Biotechnology ; Drug Resistance, Microbial/drug effects ; Humans ; Immunity/drug effects ; Inventions ; Mice ; Public Health
Chemical Substances	Anti-Infective Agents
Language	English
Publishing date	2014-04-08
Publishing country	United States
Document type	Editorial ; Introductory Journal Article
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2014/524785
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Article ; Online: Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial.

Padmapriyadarsini, Chandrasekaran / Bhavani, Perumal K / Natrajan, Mohan / Ponnuraja, Chinnayan / Kumar, Hemanth / Gomathy, Sivaramakrishnan N / Guleria, Randeep / Jawahar, Shaheed M / Singh, Manjula / Balganesh, Tanjore / Swaminathan, Soumya

BMJ open

2019 Volume 9, Issue 3, Page(s) e024363

Abstract: Introduction: Shorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like ...

Abstract	Introduction: Shorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study's objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB. Methods and analysis: We are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of Ethics and dissemination: The ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system. Trial registration number: CTRI/2018/01/011176; Pre-results.
MeSH term(s)	Adult ; Antibiotics, Antitubercular/administration & dosage ; Drug Combinations ; Drug Therapy, Combination ; Ethambutol/administration & dosage ; Humans ; India ; Isoniazid/administration & dosage ; Metformin/administration & dosage ; Multicenter Studies as Topic ; Mycobacterium tuberculosis/isolation & purification ; Pyrazinamide/administration & dosage ; Randomized Controlled Trials as Topic ; Rifampin/administration & dosage ; Tuberculosis, Pulmonary/drug therapy
Chemical Substances	Antibiotics, Antitubercular ; Drug Combinations ; isoniazid, pyrazinamide, rifampin drug combination ; Pyrazinamide (2KNI5N06TI) ; Ethambutol (8G167061QZ) ; Metformin (9100L32L2N) ; Isoniazid (V83O1VOZ8L) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2019-03-01
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2018-024363
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Article: Rising standards for tuberculosis drug development.

Balganesh, Tanjore S / Alzari, Pedro M / Cole, Stewart T

Trends in pharmacological sciences

2008 Volume 29, Issue 11, Page(s) 576–581

Abstract: Development of new drugs to treat tuberculosis (TB) faces even more constraints than the development of therapeutic agents for other diseases. This is due, in part, to intrinsic properties of the tubercle bacillus, such as its slow growth, phenotypic ... ...

Abstract	Development of new drugs to treat tuberculosis (TB) faces even more constraints than the development of therapeutic agents for other diseases. This is due, in part, to intrinsic properties of the tubercle bacillus, such as its slow growth, phenotypic drug resistance during persistence and the need for compounds with a novel mode of action because of the increasing prevalence of primary resistance to the current TB drugs. Demographic changes to the population of TB patients are also a confounding factor; these now include co-infection with HIV, but other elements, such as the growing type-2 diabetes epidemic, should not be ignored. Consequently, a new TB drug will not only have to pass all the safety requirements associated with prolonged administration but also have to be compatible with antiretroviral therapy and, possibly, other medications. Here, we review the changing clinical landscape of TB and outline how this needs to be taken into consideration when defining the product profile for a new TB drug, before describing recent progress.
MeSH term(s)	Animals ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Comorbidity ; Drug Design ; Drug Evaluation, Preclinical ; HIV Infections/complications ; Humans ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/drug effects ; Tuberculosis/drug therapy ; Tuberculosis/epidemiology
Chemical Substances	Antitubercular Agents
Language	English
Publishing date	2008-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2008.08.001
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Article ; Online: Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity.

Landge, Sudhir / Ramachandran, Vasanthi / Kumar, Anupriya / Neres, João / Murugan, Kannan / Sadler, Claire / Fellows, Mick D / Humnabadkar, Vaishali / Vachaspati, Prakash / Raichurkar, Anandkumar / Sharma, Sreevalli / Ravishankar, Sudha / Guptha, Supreeth / Sambandamurthy, Vasan K / Balganesh, Tanjore S / Ugarkar, Bheemarao G / Balasubramanian, V / Bandodkar, Balachandra S / Panda, Manoranjan

ChemMedChem

2016 Volume 11, Issue 3, Page(s) 331–339

Abstract: Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro ... ...

Abstract	Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non-enzymatic, in mycobacteria prior to binding to the target of interest. From a whole-cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) of Mycobacterium tuberculosis (Mtb). The lead was found to be mutagenic to start with. Our efforts to mitigate mutagenicity resulted in the identification of 6-methyl-7-nitro-5-(trifluoromethyl)-1,3-benzothiazoles (cBTs), a novel class of antitubercular agents that are non-mutagenic and exhibit an improved safety profile. The methyl group ortho to the nitro group decreases the electron affinity of the series, and is hence responsible for the non-mutagenic nature of these compounds. Additionally, the co-crystal structure of cBT in complex with Mtb DprE1 established the mode of binding. This investigation led to a new non-mutagenic antitubercular agent and demonstrates that the mutagenic nature of nitroarenes can be solved by modulation of stereoelectronic properties.
MeSH term(s)	Antitubercular Agents/adverse effects ; Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Benzothiazoles/adverse effects ; Benzothiazoles/chemistry ; Benzothiazoles/pharmacology ; Dose-Response Relationship, Drug ; Microbial Sensitivity Tests ; Molecular Structure ; Mutagens/chemistry ; Mycobacterium tuberculosis/drug effects ; Nitro Compounds/adverse effects ; Nitro Compounds/chemistry ; Nitro Compounds/pharmacology ; Stereoisomerism ; Structure-Activity Relationship
Chemical Substances	Antitubercular Agents ; Benzothiazoles ; Mutagens ; Nitro Compounds
Language	English
Publishing date	2016-02-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.201500462
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Article ; Online: Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis.

Shirude, Pravin S / Madhavapeddi, Prashanti / Tucker, Julie A / Murugan, Kannan / Patil, Vikas / Basavarajappa, Halesha / Raichurkar, Anandkumar V / Humnabadkar, Vaishali / Hussein, Syeed / Sharma, Sreevalli / Ramya, V K / Narayan, Chandan B / Balganesh, Tanjore S / Sambandamurthy, Vasan K

ACS chemical biology

2013 Volume 8, Issue 3, Page(s) 519–523

Abstract: Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal ... ...

Abstract	Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.
MeSH term(s)	DNA Gyrase/metabolism ; Dose-Response Relationship, Drug ; Models, Molecular ; Molecular Structure ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/growth & development ; Pyrazines/chemistry ; Pyrazines/pharmacology ; Structure-Activity Relationship ; Topoisomerase II Inhibitors/chemistry ; Topoisomerase II Inhibitors/pharmacology
Chemical Substances	Pyrazines ; Topoisomerase II Inhibitors ; DNA Gyrase (EC 5.99.1.3)
Language	English
Publishing date	2013-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb300510w
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Article ; Online: Assay development for identifying inhibitors of the mycobacterial FadD32 activity.

Galandrin, Ségolène / Guillet, Valérie / Rane, Rajendra S / Léger, Mathieu / N, Radha / Eynard, Nathalie / Das, Kaveri / Balganesh, Tanjore S / Mourey, Lionel / Daffé, Mamadou / Marrakchi, Hedia

Journal of biomolecular screening

2013 Volume 18, Issue 5, Page(s) 576–587

Abstract: FadD32, a fatty acyl-AMP ligase (FAAL32) involved in the biosynthesis of mycolic acids, major and specific lipid components of the mycobacterial cell envelope, is essential for the survival of Mycobacterium tuberculosis, the causative agent of ... ...

Abstract	FadD32, a fatty acyl-AMP ligase (FAAL32) involved in the biosynthesis of mycolic acids, major and specific lipid components of the mycobacterial cell envelope, is essential for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis. The protein catalyzes the conversion of fatty acid to acyl-adenylate (acyl-AMP) in the presence of adenosine triphosphate and is conserved in all the mycobacterial species sequenced so far, thus representing a promising target for the development of novel antituberculous drugs. Here, we describe the optimization of the protein purification procedure and the development of a high-throughput screening assay for FadD32 activity. This spectrophotometric assay measuring the release of inorganic phosphate was optimized using the Mycobacterium smegmatis FadD32 as a surrogate enzyme. We describe the use of T m (melting temperature) shift assay, which measures the modulation of FadD32 thermal stability, as a tool for the identification of potential ligands and for validation of compounds as inhibitors. Screening of a selected library of compounds led to the identification of five novel classes of inhibitors.
MeSH term(s)	Antitubercular Agents/isolation & purification ; Antitubercular Agents/pharmacology ; Chromatography, Thin Layer/methods ; Drug Discovery/methods ; High-Throughput Screening Assays/methods ; Ligases/antagonists & inhibitors ; Ligases/genetics ; Ligases/metabolism ; Models, Biological ; Mycobacterium smegmatis/enzymology ; Mycobacterium smegmatis/genetics ; Mycobacterium smegmatis/metabolism ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/genetics ; Mycolic Acids/metabolism ; Protein Binding ; Recombinant Proteins/antagonists & inhibitors ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Substrate Specificity ; Validation Studies as Topic
Chemical Substances	Antitubercular Agents ; Mycolic Acids ; Recombinant Proteins ; Ligases (EC 6.-)
Language	English
Publishing date	2013-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1433680-7
ISSN	1552-454X ; 1087-0571
ISSN (online)	1552-454X
ISSN	1087-0571
DOI	10.1177/1087057112474691
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