Developments in Chemical Approaches to Treat Tuberculosis in the Last Decade

Tripathi, Renu; Bisht, Sandeep; Aseri, Ajay; Sharma, Akanksha; Misra, Milind; Gupt, M. Pd.

doi:10.2174/092986712798918815

Cited by 14 publications

(9 citation statements)

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“…Therefore, therapeutic approaches against mycobacteria may have this defense system as a target. Indeed, effective antimicrobial strategies have been developed in the past along this line, even though in recent years the emergence of antibiotic resistant strains of M. tuberculosis required a heavy effort to find new drugs to fight the high incidence of mycobacterial diseases against immunodepressed patients [1], [5]–[7], [9], [10].…”

Section: Discussionmentioning

confidence: 99%

“…Although host genetic factors may probably contribute, the incomplete and inadequate treatment is the most important factor leading to the development of MDR-TB and XDR-TB [7], [9]–[15]. The selection and transmission of multidrug-resistant tuberculosis indicates the resistance to at least isoniazid and rifampicin, the two fundamental components of any regimen for the treatment of drug-susceptible tuberculosis [16]–[19].…”

Section: Introductionmentioning

confidence: 99%

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Isoniazid Inhibits the Heme-Based Reactivity of Mycobacterium tuberculosis Truncated Hemoglobin N

et al. 2013

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Isoniazid represents a first-line anti-tuberculosis medication in prevention and treatment. This prodrug is activated by a mycobacterial catalase-peroxidase enzyme called KatG in Mycobacterium tuberculosis), thereby inhibiting the synthesis of mycolic acid, required for the mycobacterial cell wall. Moreover, isoniazid activation by KatG produces some radical species (e.g., nitrogen monoxide), that display anti-mycobacterial activity. Remarkably, the ability of mycobacteria to persist in vivo in the presence of reactive nitrogen and oxygen species implies the presence in these bacteria of (pseudo-)enzymatic detoxification systems, including truncated hemoglobins (trHbs). Here, we report that isoniazid binds reversibly to ferric and ferrous M. tuberculosis trHb type N (or group I; Mt-trHbN(III) and Mt-trHbN(II), respectively) with a simple bimolecular process, which perturbs the heme-based spectroscopic properties. Values of thermodynamic and kinetic parameters for isoniazid binding to Mt-trHbN(III) and Mt-trHbN(II) are K = (1.1±0.1)×10−4 M, k on = (5.3±0.6)×103 M−1 s−1 and k off = (4.6±0.5)×10−1 s−1; and D = (1.2±0.2)×10−3 M, d on = (1.3±0.4)×103 M−1 s−1, and d off = 1.5±0.4 s−1, respectively, at pH 7.0 and 20.0°C. Accordingly, isoniazid inhibits competitively azide binding to Mt-trHbN(III) and Mt-trHbN(III)-catalyzed peroxynitrite isomerization. Moreover, isoniazid inhibits Mt-trHbN(II) oxygenation and carbonylation. Although the structure of the Mt-trHbN-isoniazid complex is not available, here we show by docking simulation that isoniazid binding to the heme-Fe atom indeed may take place. These data suggest a direct role of isoniazid to impair fundamental functions of mycobacteria, e.g. scavenging of reactive nitrogen and oxygen species, and metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Isoniazid Inhibits the Heme-Based Reactivity of Mycobacterium tuberculosis Truncated Hemoglobin N

et al. 2013

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“…Compound 37 is a rare example of antitubercular agent possessing in its structure the guanidine motif. This structural motif is common in antibiotics like streptomycin, capreomycin, viomycin [3,15] and some synthetic polyamines [16].…”

Section: In Vitro Antimycobacterial Activitymentioning

confidence: 98%

“…Potential anti-TB drug candidates such as diarylquinolones (TMC207), nitroimidazoles (OPC67683 and PA824), pyrroles (LL3858), diamines [2] are in different stages of clinical trials [3,4]. The incorporation of lipophilic polycyclic aliphatic compounds into drug-structures with promising anti-TB applications has enjoyed much attention from researchers for several years starting with the discovery of SQ109 [5].…”

Section: Introductionmentioning

confidence: 99%

Enantiopure antituberculosis candidates synthesized from (−)-fenchone

Dobrikov

Valcheva

Nikolova

et al. 2014

European Journal of Medicinal Chemistry

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“…Combination chemotherapy with anti-TB drugs (isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months and isoniazid and rifampicin for 4 months) is the mainstay of TB treatment [2]. Most TB cases are cured using routine anti-TB therapy, but some TB patients may develop severe side effects [3–5] or drug-resistant TB [4, 6]. The adverse effects of anti-TB drugs vary greatly among individuals [2, 7], and these effects are closely related to disease progression and the immune status of the patient [8].…”

Section: Introductionmentioning

confidence: 99%

Microarray expression profile analysis of mRNAs and long non-coding RNAs in pulmonary tuberculosis with different traditional Chinese medicine syndromes

Wei

Shi

Chen

et al. 2016

BMC Complement Altern Med

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BackgroundCombination chemotherapy with Western anti-tuberculosis (TB) drugs is the mainstay of TB treatment. Chinese herbal medicines with either heat clearing and detoxifying effects or nourishing Yin and reducing fire effects have been used to treat TB based on the Traditional Chinese Medicine (TCM) syndromes of TB patients. This study analyzed the expression profiles of long non-coding RNAs (lncRNAs) and mRNAs in TB patients with different TCM syndromes.MethodsTB patients were classified as pulmonary Yin deficiency (PYD) syndrome, hyperactivity of fire due to Yin deficiency (HFYD) syndrome, and deficiency of Qi and Yin (DQY) syndrome. Total RNA from 44 TB patients and healthy controls was extracted and hybridized with a human lncRNA microarray containing 30586 lncRNAs and 26109 mRNAs probes. Bioinformatics analyses, including gene ontology (GO) and pathways, were performed. Related clinical data were also analyzed.ResultsDifferentially expressed mRNAs and lncRNAs were identified (fold change >2, and P < 0.05) in PYD (634 mRNAs and 566 lncRNAs), HFYD (47 mRNAs and 55 lncRNAs), and DQY (63 mRNAs and 60 lncRNAs) patients. The most enriched pathways were the hippo signaling pathway (P = 0.000164) and the protein digestion and absorption pathway (P = 5.89017E-05). Clinical analyses revealed that the lipid indexes of TB patients were abnormal and that the triglyceride concentration was significantly higher in DQY patients (P = 0.0252). Our study is the first to acquire the microarray expression profiles of lncRNAs and mRNAs and analyze pathway enrichment in PYD, HFYD, and DQY patients with TB.ConclusionsOur analyses of the expression profiles of lncRNAs and mRNAs may represent a novel method to explore the biological essence of TCM syndromes of TB.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1436-y) contains supplementary material, which is available to authorized users.

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Developments in Chemical Approaches to Treat Tuberculosis in the Last Decade

Cited by 14 publications

References 0 publications

Isoniazid Inhibits the Heme-Based Reactivity of Mycobacterium tuberculosis Truncated Hemoglobin N

Isoniazid Inhibits the Heme-Based Reactivity of Mycobacterium tuberculosis Truncated Hemoglobin N

Enantiopure antituberculosis candidates synthesized from (−)-fenchone

Microarray expression profile analysis of mRNAs and long non-coding RNAs in pulmonary tuberculosis with different traditional Chinese medicine syndromes

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