Drug targets exploited in Mycobacterium tuberculosis: Pitfalls and promises on the horizon

Bhat, Zubair Shanib; Rather, Muzafar Ahmad; Maqbool, Mubashir; Ahmad, Zahoor

doi:10.1016/j.biopha.2018.04.176

Cited by 39 publications

(30 citation statements)

References 185 publications

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“…The intensive phase reduces the bacillary load by killing about 95% of the microorganisms, while the continuation phase focuses on eliminating the drug-sensitive organisms [ 24 ]. This treatment regimen successfully achieves an 85% success rate for new TB cases as reported by the WHO [ 25 ]. Despite the high success rate, HRZE contributes to several adverse events, including hepatotoxicity, hyperuricemia, peripheral neuritis, hypersensitivity, visual toxicity, cutaneous reactions, flu-like syndrome, ototoxicity, fever, gastrointestinal intolerance, and psychiatric changes.…”

Section: Current Antituberculosis Drugsmentioning

confidence: 81%

Antituberculosis Targeted Drug Delivery as a Potential Future Treatment Approach

et al. 2021

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Mycobacterium tuberculosis (Mtb) is the microorganism that causes tuberculosis. This infectious disease has been around for centuries, with the earliest record of Mtb around three million years ago. The discovery of the antituberculosis agents in the 20th century has managed to improve the recovery rate and reduce the death rate tremendously. However, the conventional antituberculosis therapy is complicated by the development of resistant strains and adverse drug reactions experienced by the patients. Research has been conducted continuously to discover new, safe, and effective antituberculosis drugs. In the last 50 years, only two molecules were approved despite laborious work and costly research. The repurposing of drugs is also being done with few drugs; antibiotics, particularly, were found to have antituberculosis activity. Besides the discovery work, enhancing the delivery of currently available antituberculosis drugs is also being researched. Targeted drug delivery may be a potentially useful approach to be developed into clinically accepted treatment modalities. Active targeting utilizes a specifically designed targeting agent to deliver a chemically conjugated drug(s) towards Mtb. Passive targeting is very widely explored, with the development of multiple types of nanoparticles from organic and inorganic materials. The nanoparticles will be engulfed by macrophages and this will eliminate the Mtb that is present in the macrophages, or the encapsulated drug may be released at the sites of infections that may be in the form of intra- and extrapulmonary tuberculosis. This article provided an overview on the history of tuberculosis and the currently available treatment options, followed by discussions on the discovery of new antituberculosis drugs and active and passive targeting approaches against Mycobacterium tuberculosis.

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Section: Current Antituberculosis Drugsmentioning

confidence: 81%

Antituberculosis Targeted Drug Delivery as a Potential Future Treatment Approach

et al. 2021

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“…The pro-drug isoniazid, inhibits the NADH-dependent enoyl-acyl carrier protein (ACP) reductase (InhA), encoded by inhA , but its clinical utility is hampered by the high frequency of mutations in activation the catalase-peroxidase (KatG) required for its activation ( Bhat et al., 2018 ) and the wide variation in the human N-acetyltransferases that catalyze drug metabolism ( Sim et al., 2014 ). Identification of InhA inhibitors that do not require activation of the pro-drug and lack variable human metabolism would be of substantial clinical utility of isoniazid while overcoming the problem of high resistance frequencies.…”

Section: Antitubercular Agents Inhibiting Mycolic Acid Biosynthesismentioning

confidence: 99%

Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

Trifonov

Yadav

et al. 2021

Front. Cell. Infect. Microbiol.

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More than two decades have elapsed since the publication of the first genome sequence of Mycobacterium tuberculosis (Mtb) which, shortly thereafter, enabled methods to determine gene essentiality in the pathogen. Despite this, target-based approaches have not yielded drugs that have progressed to clinical testing. Whole-cell screening followed by elucidation of mechanism of action has to date been the most fruitful approach to progressing inhibitors into the tuberculosis drug discovery pipeline although target-based approaches are gaining momentum. This review discusses scaffolds that have been identified over the last decade from screens of small molecule libraries against Mtb or defined targets where mechanism of action investigation has defined target-hit couples and structure-activity relationship studies have described the pharmacophore.

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“…All bacteria require energy to function. In aerobic organisms, the process of oxidative phosphorylation (the conversion of chemical energy from diverse sources of ATP) can be altered in M. tuberculosis to interfere with bacterial metabolism [33]. Folate or vitamin B9 is very important in prokaryotes, including Mycobacterium.…”

Section: Therapeutic Targetsmentioning

confidence: 99%

“…Various molecular targets against M. tuberculosis exist; those targets include DNA replication, RNA synthesis, energy metabolism, folate metabolism, and bacterial cell wall synthesis [ 33 ]. Mycobacterial cell wall inhibitors impede the synthesis of mycolic acids, arabinogalactan and peptidoglycan, important components of the mycobacterial cell wall [ 34 ].…”

Section: Therapeutic Targetsmentioning

confidence: 99%

The War against Tuberculosis: A Review of Natural Compounds and Their Derivatives

et al. 2020

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Tuberculosis (TB), caused by the bacterial organism Mycobacterium tuberculosis, pose a major threat to public health, especially in middle and low-income countries. Worldwide in 2018, approximately 10 million new cases of TB were reported to the World Health Organization (WHO). There are a limited number of medications available to treat TB; additionally, multi-drug resistant TB and extensively-drug resistant TB strains are becoming more prevalent. As a result of various factors, such as increased costs of developing new medications and adverse side effects from current medications, researchers continue to evaluate natural compounds for additional treatment options. These substances have the potential to target bacterial cell structures and may contribute to successful treatment. For example, a study reported that green and black tea, which contains epigallocatechin gallate (a phenolic antioxidant), may decrease the risk of contracting TB in experimental subjects; cumin (a seed from the parsley plant) has been demonstrated to improve the bioavailability of rifampicin, an important anti-TB medication, and propolis (a natural substance produced by honeybees) has been shown to improve the binding affinity of anti-TB medications to bacterial cell structures. In this article, we review the opportunistic pathogen M. tuberculosis, various potential therapeutic targets, available therapies, and natural compounds that may have anti-TB properties. In conclusion, different natural compounds alone as well as in combination with already approved medication regimens should continue to be investigated as treatment options for TB.

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Drug targets exploited in Mycobacterium tuberculosis: Pitfalls and promises on the horizon

Cited by 39 publications

References 185 publications

Antituberculosis Targeted Drug Delivery as a Potential Future Treatment Approach

Antituberculosis Targeted Drug Delivery as a Potential Future Treatment Approach

Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

The War against Tuberculosis: A Review of Natural Compounds and Their Derivatives

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