Attack on the Scourge of Tuberculosis: Patented Drug Targets (original) (raw)
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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...
Novel targets for tuberculosis drug discovery
Current opinion in pharmacology, 2006
Since the determination of the Mycobacterium tuberculosis genome sequence, various groups have used the genomic information to identify and validate targets as the basis for the development of new anti-tuberculosis agents. Validation might include many components: demonstration of the biochemical activity of the enzyme, determination of its crystal structure in complex with an inhibitor or a substrate, confirmation of essentiality, and the identification of potent growth inhibitors either in vitro or in an infection model. If novel target validation and subsequent inhibition are matched by an improved understanding of disease biology, then new antibiotics could have the potential to shorten the duration of therapy, prevent resistance development and eliminate latent disease.
Discovery of Common Putative Drug Targets and Vaccine Candidates for Mycobacterium tuberculosis sp
Journal of Drug Delivery and Therapeutics, 2019
Mycobacterium tuberculosis is the bacteria that cause tuberculosis (TB), an infection that usually affects the lungs and can be fatal without proper treatment. Combating through available drugs became a difficult task due to drug resistance and lack of appropriate common targets against genetically diverse strains. Since to improve efficacy, the effective targets should be identified and critically assessed. In the study, we aim to predict the potential novel targets against M. tuberculosis strains by employing in silico approach. The complete proteomic datasets of 23 M. tuberculosis strains was comparatively processed by executing R-scripts and eventually predicted 3906 'conserved gene products'. Further, we performed subtractive proteomic approach in search of promising crucial targets. Consequently, eight enzymes and two membrane proteins were prioritized as new therapeutic and vaccine targets respectively which found to have more interactors in network with high-confiden...
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
Tuberculosis (TB) is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS with 6.3 million new cases of TB reported in 2016. TB is an airborne disease associated with the aerobic bacterium Mycobacterium tuberculosis (Mtb), which mainly infects the lungs. Aerosolization of diseased pulmonary secretions, by coughing, sneezing and speaking, discharge the Mtb bacilli into the atmosphere. Infected aerosol droplet nuclei sized 1-μm are largely trapped in the upper nasal passages or are expelled into the pharynx by the mucociliary mechanism of the lower respiratory tract and are harmlessly swallowed and digested. Infected persons may overcome the initial TB infection, resulting in the development of asymptomatic latent TB. About 10% of individuals may develop the active disease after infection; where the bacteria undergo more rapid growth and overcome the host immune system. In cases of multi-drug resistant (MDR) strains, and extreme drug-resistant (XDR) strains, treatment fails, and the bacteria propagate and attack the host, leading to death from systemic infection. Due to the increased spread of TB worldwide, both the academic and industrial communities have initiated intensive research to develop new therapeutics targeting new enzymes such as cytochrome P450s in Mtb.
Novel drug target strategies against Mycobacterium tuberculosis Curr Op Microbiology 2008
The resurgence of drug resistant tuberculosis (TB) is a significant global healthcare challenge. Mycobacterium tuberculosis (MTB), TB's causative agent, evades the host immune system and drug regimes by entering prolonged periods of non-proliferation or dormancy. In infected individuals, the immune system sequesters MTB into structures called granulomas where the bacterium survives by shifting into a non-replicative state. Although still not well understood, progress has been made in characterizing the genetic program of MTB, activated by DosR (DevR) signal transduction that allows adaptation to the hypoxic, nutrient limiting granuloma microenvironment. Recent work, especially the identification genes involved in regulatory networks and the Enduring Hypoxic Response (EHR), hold promise for developing new drugs targeting dormancy phase MTB.
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.
Challenges in Drug Discovery against Tuberculosis
Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex, 2021
Tuberculosis (TB) is one of the deadly diseases in the present era caused by Mycobacterium tuberculosis. Principally, this bacterium attacks the lungs, however, MTB Has been observed affecting any part of the human body including the kidney, spine, and brain. Drug-resistant progression and other associated properties of MTB become a major hurdle in drug discovery to fight against tuberculosis. Moreover, some of the challenging situations such as the low range of chemical agents, the time-consuming process of drug development, the shortage of predictive animal models, and inadequate information of the physicochemical evidence required for effective bacterial penetration, are additional hindrances for the pharmaceutical scientist. In the current chapter, we focus on challenges encountered during drug discovery and need to be overcome as M. tuberculosis has a substantial barrier in its lipid-containing cell wall to inhibit the influx of drugs which is the initial requirement of the dru...
PLoS Pathogens, 2014
Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if appropriately activated. The outcome of infection is determined at least in part by the host-pathogen interaction within the macrophage; however, we lack a complete understanding of which host pathways are critical for bacterial survival and replication. To add to our understanding of the molecular processes involved in intracellular infection, we performed a chemical screen using a high-content microscopic assay to identify small molecules that restrict mycobacterial growth in macrophages by targeting host functions and pathways. The identified host-targeted inhibitors restrict bacterial growth exclusively in the context of macrophage infection and predominantly fall into five categories: G-protein coupled receptor modulators, ion channel inhibitors, membrane transport proteins, antiinflammatories, and kinase modulators. We found that fluoxetine, a selective serotonin reuptake inhibitor, enhances secretion of pro-inflammatory cytokine TNF-a and induces autophagy in infected macrophages, and gefitinib, an inhibitor of the Epidermal Growth Factor Receptor (EGFR), also activates autophagy and restricts growth. We demonstrate that during infection signaling through EGFR activates a p38 MAPK signaling pathway that prevents macrophages from effectively responding to infection. Inhibition of this pathway using gefitinib during in vivo infection reduces growth of M. tuberculosis in the lungs of infected mice. Our results support the concept that screening for inhibitors using intracellular models results in the identification of tool compounds for probing pathways during in vivo infection and may also result in the identification of new anti-tuberculosis agents that work by modulating host pathways. Given the existing experience with some of our identified compounds for other therapeutic indications, further clinically-directed study of these compounds is merited.