Novel targets for tuberculosis drug discovery (original) (raw)
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Analysis novel drug target enzymes in Mycobacterium tuberculosis
2011
My thanks go out to my friends and colleagues in the Munro, Scrutton, and Leys groups for all their help, discussions, and communication. Finally, I would like to thank my family, my parents, and my wife who give me a great support and understanding for my studies in Manchester.
Identification and validation of novel drug targets in Mycobacterium tuberculosis
Tuberculosis (TB) is a global epidemic associated increasingly with resistance to first-and second-line antitubercular drugs. The magnitude of this global health threat underscores the urgent need to discover new antimycobacterial agents that have novel mechanisms of action (MOA). In this review, we highlight some of the key advances that have enabled the strengths of target-led and phenotypic approaches to TB drug discovery to be harnessed both independently and in combination. Critically, these promise to fuel the front-end of the TB drug pipeline with new, pharmacologically validated drug targets together with lead compounds that act on these targets. Corresponding author: Singh, V. (vinayak.singh@uct.ac.za) 1359-6446/ß
The Journal of infectious diseases, 2012
There is an increasing flow of new antituberculosis chemical entities entering the tuberculosis drug development pipeline. Although this is encouraging, the current number of compounds is too low to meet the demanding criteria required for registration, shorten treatment duration, treat drug-resistant infection, and address pediatric tuberculosis cases. More new chemical entities are needed urgently to supplement the pipeline and ensure that more drugs and regimens enter clinical practice. Most drug discovery projects under way exploit enzyme systems deemed essential in a specific Mycobacterium tuberculosis biosynthetic pathway or develop chemical scaffolds identified by phenotypic screening of compound libraries, specific pharmacophores or chemical clusters, and natural products. Because the development of a compound for treating tuberculosis is even longer than for treating other infection indications, the identification of selective, potent, and safe chemical entities early in th...
New drug targets for Mycobacterium tuberculosis
The Indian journal of medical research, 2003
In spite of the availability of effective chemotherapy and Bacille-Calmette-Guerin (BCG) vaccine, tuberculosis remains a leading infectious killer world-wide. Many factors such as, human immunodeficiency virus (HIV) co-infection, drug resistance, lack of patient compliance with chemotherapy, delay in diagnosis, variable efficacy of BCG vaccine and various other factors contribute to the mortality due to tuberculosis. In spite of the new advances in understanding the biology of Mycobacterium tuberculosis, and availability of functional genomic tools, such as microarray and proteomics, in combination with modern approaches, no new drug has been developed in the past 30 yr. Therefore, there is an urgent need to identify new drug targets in mycobacteria and eventually, develop new drugs. The release of the complete genome sequence of M. tuberculosis has facilitated a more rational, and directional approach to search for new drug targets. In general, gene products involved in mycobacteri...
Challenges in the development of drugs for the treatment of tuberculosis
The Brazilian Journal of Infectious Diseases, 2013
Tuberculosis infection is a serious human health threat and the early 21st century has seen a remarkable increase in global tuberculosis activity. The pathogen responsible for tuberculosis is Mycobacterium tuberculosis, which adopts diverse strategies in order to survive in a variety of host lesions. These survival mechanisms make the pathogen resistant to currently available drugs, a major contributing factor in the failure to control the spread of tuberculosis. Multiple drugs are available for clinical use and several potential compounds are being screened, synthesized, or evaluated in preclinical or clinical studies. Lasting and effective achievements in the development of anti-tuberculosis drugs will depend largely on the proper understanding of the complex interactions between the pathogen and its human host. Ample evidence exists to explain the characteristics of tuberculosis. In this study, we highlighted the challenges for the development of novel drugs with potent bacteriostatic or bactericidal activity, which reduce the minimum time required to cure tuberculosis infection.
Large-scale chemical-genetics yields new Mycobacterium tuberculosis inhibitor classes
2018
New antibiotics are needed to combat rising resistance, with new Mycobacterium tuberculosis (Mtb) drugs of highest priority. Conventional whole-cell and biochemical antibiotic screens have failed. We developed a novel strategy termed PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) in which we screen compounds against pools of strains depleted for essential bacterial targets. We engineered strains targeting 474 Mtb essential genes and screened pools of 100-150 strains against activity-enriched and unbiased compounds libraries, measuring > 8.5-million chemical-genetic interactions. Primary screens identified >10-fold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insight. We identified > 40 novel compounds targeting DNA gyrase, cell wall, tryptophan, folate biosynthesis, and RNA polymerase, as well as inhibitors of a novel target EfpA. Chemical optimization yielded EfpA i...
Rational Drug Designing Strategies for Mycobacterium Tuberculosis
Despite the availability of various techniques for diagnosis; the presence of improved and modified version of vaccines and the existence of more than a dozen of drugs, tuberculosis still remains as a significant infectious disease. The publication of complete genome of Mycobacterium tuberculosis has lead to the development of new genetic tools to ascertain the functioning of individual genes, leading to subsequent identification and validation of potential drug targets. With the help of Rational Drug designing, a computer-aided approach to find molecules with desired chemical and geometric properties that bind in a receptor cavity of specific target protein. It is hoped that promising new drugs for the effective treatment of not only TB also for MDR, XDR, HIV and persistent TB will be possible in the near future.