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Indole-3-Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target.
Esposito, N, Konas, DW, Goodey, NM
Chembiochem : a European journal of chemical biology. 2022;(2):e202100314
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Abstract
Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, affects millions of people worldwide. Several TB drugs have lost efficacy due to emerging drug resistance and new anti-TB targets are needed. Recent research suggests that indole-3-glycerol phosphate synthase (IGPS) in M. tuberculosis (MtIGPS) could be such a target. IGPS is a (β/α)8 -barrel enzyme that catalyzes the conversion of 1-(o-carboxyphenylamino)-1-deoxyribulose 5'-phosphate (CdRP) into indole-glycerol-phosphate (IGP) in the bacterial tryptophan biosynthetic pathway. M. tuberculosis over expresses the tryptophan pathway genes during an immune response and inhibition of MtIGPS allows CD4 T-cells to more effectively fight against M. tuberculosis. Here we review the published data on MtIGPS expression, kinetics, mechanism, and inhibition. We also discuss MtIGPS crystal structures and compare them to other IGPS structures to reveal potential structure-function relationships of interest for the purposes of drug design and biocatalyst engineering.
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Collocating Novel Targets for Tuberculosis (TB) Drug Discovery.
Gandhi, K, Patel, M
Current drug discovery technologies. 2021;(2):307-316
Abstract
BACKGROUND Mycobacterium tuberculosis, being a resistive species is an incessant threat to the world population for the treatment of Tuberculosis (TB). An advanced genetic or a molecular level approach is mandatory for both diagnosis and therapy as the prevalence of multi drug-resistant (MDR) and extensively drug- resistant (XDR) TB. METHODS A literature review was conducted, focusing essentially on the development of biomarkers and targets to extrapolate the Tuberculosis Drug Discovery process. RESULTS AND DISCUSSION In this article, we have discussed several substantial targets and genetic mutations occurring in a diseased or treatment condition of TB patients. It includes expressions in Bhlhe40, natural resistance associated macrophage protein 1 (NRAMP1) and vitamin D receptor (VDR) with its mechanistic actions that have made a significant impact on TB. Moreover, recently identified compounds; imidazopyridine amine derivative (Q203), biphenyl amide derivative (DG70), azetidine, thioquinazole, tetrahydroindazole and 2- mercapto- quinazoline scaffolds for several targets such as adenosine triphosphate (ATP), amino acid and fatty acid have been briefed for their confirmed hits and therapeutic activity.
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Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.
Mitini-Nkhoma, SC, Chimbayo, ET, Mzinza, DT, Mhango, DV, Chirambo, AP, Mandalasi, C, Lakudzala, AE, Tembo, DL, Jambo, KC, Mwandumba, HC
Frontiers in immunology. 2021;:665785
Abstract
Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb's differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host's antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.
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Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival.
Yelamanchi, SD, Surolia, A
IUBMB life. 2021;(4):643-658
Abstract
Tuberculosis caused by the bacterium, Mycobacterium tuberculosis (Mtb), continues to remain one of the most devastating infectious diseases afflicting humans. Although there are several drugs for treating tuberculosis available currently, the emergence of the drug resistant forms of this pathogen has made its treatment and eradication a challenging task. While the replication machinery, protein synthesis and cell wall biogenesis of Mtb have been targeted often for anti-tubercular drug development a number of essential metabolic pathways crucial to its survival have received relatively less attention. In this context a number of amino acid biosynthesis pathways have recently been shown to be essential for the survival and pathogenesis of Mtb. Many of these pathways and or their key enzymes homologs are absent in humans hence they could be harnessed for anti-tubercular drug development. In this review, we describe comprehensively the amino acid metabolic pathways essential in Mtb and the key enzymes involved therein that are being investigated for developing inhibitors that compromise the survival and pathogenesis caused by this pathogen.
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Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design.
Kamariah, N, Ragunathan, P, Shin, J, Saw, WG, Wong, CF, Dick, T, Grüber, G
Progress in biophysics and molecular biology. 2020;:64-73
Abstract
The causative agent of Tuberculosis (TB) Mycobacterium tuberculosis (Mtb) encounters unfavourable environmental conditions in the lungs, including nutrient limitation, low oxygen tensions and/or low/high pH values. These harsh conditions in the host triggers Mtb to enter a dormant state in which the pathogen does not replicate and uses host-derived fatty acids instead of carbohydrates as an energy source. Independent to the energy source, the bacterium's energy currency ATP is generated by oxidative phosphorylation, in which the F1FO-ATP synthase uses the proton motive force generated by the electron transport chain. This catalyst is essential in Mtb and inhibition by the diarylquinoline class of drugs like Bedaquilline, TBAJ-587, TBAJ-876 or squaramides demonstrated that this engine is an attractive target in TB drug discovery. A special feature of the mycobacterial F-ATP synthase is its inability to establish a significant proton gradient during ATP hydrolysis, and its latent ATPase activity, to prevent energy waste and to control the membrane potential. Recently, unique epitopes of mycobacterial F1FO-ATP synthase subunits absent in their prokaryotic or mitochondrial counterparts have been identified to contribute to the regulation of the low ATPase activity. Most recent structural insights into individual subunits, the F1 domain or the entire mycobacterial enzyme added to the understanding of mechanisms, regulation and differences of the mycobacterial F1FO-ATP synthase compared to other bacterial and eukaryotic engines. These novel insights provide the basis for the design of new compounds targeting this engine and even novel regimens for multidrug resistant TB.
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Pulmonary tuberculosis presenting as henoch-schönlein purpura: Case report and literature review.
Li, J, Wang, XZ, Wang, RC, Yang, J, Hao, HL, Xue, LY
Medicine. 2020;(40):e22583
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Abstract
INTRODUCTION Henoch-Schönlein purpura (HSP) is an extremely rare condition in patients with pulmonary tuberculosis, with only a few reported cases. Compared to patients with typical clinical symptoms, it is difficult to make a definitive diagnosis when HSP presents as an initial manifestation in pulmonary tuberculosis patients. Herein, a case of pulmonary tuberculosis that showed HSP at first was reported, and the related literatures were reviewed. PATIENT CONCERNS A 24-year-old man presented with palpable purpura on the extremities, accompanied by abdominal pain, bloody stools, and knee pain. DIAGNOSES The patient was diagnosed with pulmonary tuberculosis based on the results of interferon gamma release assays, purified protein derivative test, and computed tomography. INTERVENTIONS The patient was treated with vitamin C and chlorpheniramine for 2 weeks, and the above-mentioned symptoms were relieved. However, 3 weeks later, the purpura recurred with high-grade fever and chest pain during the inspiratory phase. The patient was then treated with anti-tuberculosis drugs, and the purpura as well as the high fever disappeared. OUTCOMES The patient recovered well and remained free of symptoms during the follow-up examination. CONCLUSION Pulmonary tuberculosis presenting with HSP as an initial manifestation is not common. Therefore, it is difficult to clinically diagnose and treat this disease. When an adult patient shows HSP, it is important to consider the possibility of tuberculosis to avoid misdiagnosis and delayed treatment.
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Potential drug targets in the Mycobacterium tuberculosis cytochrome P450 system.
Ortiz de Montellano, PR
Journal of inorganic biochemistry. 2018;:235-245
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Abstract
The Mycobacterium tuberculosis genome encodes twenty cytochrome P450 enzymes, most or all of which appear to have specific physiological functions rather than being devoted to the removal of xenobiotics. However, in many cases their specific functions remain obscure. Considerable spectroscopic, biophysical, crystallographic, and catalytic information is available on nine of these cytochrome P450 enzymes, although gaps exist in our knowledge of even these enzymes. The available evidence indicates that at least three of the better-characterized enzymes are promising targets for antituberculosis drug discovery. This review summarizes the information on the nine relatively well-characterized cytochrome P450 enzymes, with a particular emphasis on CYP121, CYP125, and CYP142 from Mycobacterium tuberculosis and Mycobacterium smegmatis.
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Vitamins Based Novel Target Pathways/Molecules as Possible Emerging Drug Targets for the Management of Tuberculosis.
Sharma, A, Jain, K, Flora, SJS
Medicinal chemistry (Shariqah (United Arab Emirates)). 2018;(3):212-224
Abstract
BACKGROUND Tuberculosis (TB) is a deadly infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). Approximately, 1.8 and 1.3 million people are infected and die, from TB each year as estimated by the World Health Organization. Due to increase in the incidence of drug-resistant strains of Mtb, there is an urgent need to accelerate research which focuses on the development of new drugs with novel mechanism of action that can treat both drugsensitive and resistant TB infections. OBJECTIVE The purpose of this review study was to describe vitamins as drug target that can be explored to develop new anti tubercular drugs that can treat both drug-sensitive and resistant TB infections. METHOD The methodological approaches include literature review which is performed in the databases like PubMed, Web of Science, Scopus, Springer and Science Direct, etc. On the basis of evaluation of literature sources, the review was complied. RESULTS This review study demonstrated that vitamins biosynthesis pathway could be used in the development of novel drug targets. Further sequencing of the Mtb genome facilitated research in target identification and validation that make possible the discovery of novel anti-TB agent with new mechanisms of action. Several compounds were identified, which target vitamin biosynthesis pathway /enzymes. Some other new targets were also identified and can be explored for the identification of novel structural moiety. CONCLUSION Further exploration of these compounds which have been identified to target these vitamins related novel target pathways /molecules could led to the development of antitubercular drug which can be used in the treatment of drug sensitive and resistant TB.
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Mycobacterium kansasii.
Johnston, JC, Chiang, L, Elwood, K
Microbiology spectrum. 2017;(1)
Abstract
The incidence of Mycobacterium kansasii varies widely over time and by region, but this organism remains one of the most clinically relevant isolated species of nontuberculous mycobacteria. In contrast to other common nontuberculous mycobacteria, M. kansasii is infrequently isolated from natural water sources or soil. The major reservoir appears to be tap water. Infection is likely acquired through the aerosol route, with low infectivity in regions of endemicity. Human-to-human transmission is thought not to occur. Clinical syndromes and radiological findings of M. kansasii infection are mostly indistinguishable from that of Mycobacterium tuberculosis, thus requiring microbiological confirmation. Disseminated disease is uncommon in HIV-negative patients and usually associated with severe immunosuppression. The majority of patients with M. kansasii pulmonary disease have underlying pulmonary comorbidities, such as smoking, chronic obstructive pulmonary disease, bronchiectasis, and prior or concurrent M. tuberculosis infection. Surveys in Great Britain, however, noted higher rates, with 8 to 9% of M. kansasii infections presenting with extrapulmonary disease. Common sites of extrapulmonary disease include the lymph nodes, skin, and musculoskeletal and genitourinary systems. The specificity of gamma interferon release assays (IGRAs) for M. tuberculosis may be reduced by M. kansasii infection, as M. kansasii encodes CFP-10 and ESAT-6, two antigens targeted by IGRAs. A study conducted to evaluate the therapy in rifampin-resistant disease found that patients with acquired rifampin resistance were treated with daily high-dose ethambutol, isoniazid, sulfamethoxazole, and pyridoxine combined with aminoglycoside therapy. Given the potential toxicities, particularly with aminoglycoside therapy, clarithromycin and/or moxifloxacin therapy could be considered as alternatives.
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An Overview of Phytotherapeutic Approaches for the Treatment of Tuberculosis.
Sharma, D, Yadav, JP
Mini reviews in medicinal chemistry. 2017;(2):167-183
Abstract
Tuberculosis (TB) is highly infectious disease causing morbidity and death. Its causative organism is a contagious bacterium, Mycobacterium tuberculosis. The incidence of tuberculosis is increasing worldwide due to the emergence of drug resistance bacteria. The resistance is being developed in Mycobacterium tuberculosis against both the first line as well as the second line drugs used for the treatment. The tuberculosis control programme is being complicated and failed to get the desired impact due to the development of multi-drug resistant (MDR) and extensively-drug resistant (XDR) strains of Mycobacterium tuberculosis. So, there is a critical requirement to discover and produce newer anti-TB drugs with unique drug targets. Medicinal plants have been used for curing the diseases from ancient time. Medicinal plants are the novel sources for the production of alternate medicines for the treatment of TB caused by MDR and XDR strains. Plants produce a number of different kinds of secondary metabolites such as Alkaloids, Coumarins, Flavonoids, Polyphenols, Terpenoids, Quinines, etc. which have antimicrobial activity; thus may be useful in control of tuberculosis. These compounds do not contribute directly in growth and development but used by the plants for their defense. On the basis of various sources in the literature, about 72 phytochemicals constituents responsible for anti tubercular activity isolated from different plants have been explained along with their structure. Most effective isolated compounds from plants are plumbagin, maritinone, 3, 3'-biplumbagin, aloe emodin, epigallocatechin and umckalin. These phytochemicals are helpful for the treatment of MDR, XDR type of tuberculosis. This review describes an overview of the current synthetic medicines used for treatment of TB and the work carried out on anti tubercular plants along with their phytochemicals.