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Role of Plant-Based Bioflavonoids in Combating Tuberculosis
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Assessment of Medicinal Plants for Human Health, 2020
Alka Pawar, Yatendra Kumar Satija
Isoniazid (INH) is a prodrug, which needs catalytic activation by the enzyme MTB catalase-peroxidase katG, which leads to the formation of INH-NAD complex. This complex prohibits the nicotinamide adenine dinucleotide (NADH)-dependent enoyl-ACP reductase, which belongs to the fatty acid synthase type II system, a key player in the mycolic acid biosynthetic pathway of MTB.86 Hence, it inhibits the synthesis of mycolic acid, that is, a cell wall component.
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
Abdullah Alsultan, Charles A. Peloquin
INH is a synthetic agent, and its pyridine nucleus and carboxylic acid hydrazide side chain both are key structural features [7–9]. INH is a pro-drug, activated within M. tuberculosis by the enzyme, katG [10–12]. INH-derived reactive intermediates that form adducts with NAD+ (nicotinamide adenine dinucleotide) and NADP+ (phosphate form), leading to a blockade of mycolic acid synthesis [12]. The katG gene encodes for mycobacterial catalase peroxidase and organisms lacking this gene do not synthesise catalase or peroxidase and generally show INH resistance. InhA, an enoyl acyl carrier protein reductase, appears to be the primary target for the INH-NAD product described earlier [13]. Resistance occurs at a rate of about one in 107 organisms.
Isoniazid
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Isoniazid inhibits the synthesis of mycolic acids, a critical component of the lipid-rich mycobacterial cell wall, and has a bactericidal action on M. tuberculosis (Takayama et al., 1972; Quémard et al., 1991). Isoniazid is a prodrug that is converted by the mycobacterial enzyme catalase peroxidase (KatG) into the active form. Various radicals of isoniazid then covalently bind to nicotinamide adenine dinucleotide (NAD), and this inhibits the product of the inhA gene, an NADH-dependent enoyl-acyl carrier protein reductase that is part of the fatty acid synthase (FAS)-II responsible for mycolic acid synthesis (Vilchèze and Jacobs, 2007). Resistance to isoniazid can therefore arise by mutations in either katG or inhA (Zhang and Young, 1994; Rouse et al., 1995), and because inhA also appears to be the target of ethionamide, cross-resistance can occur between these two drugs (see Chapter 132, Ethionamide and Prothionamide). In one study that included 403 isoniazid-resistant M. tuberculosis isolates obtained from six different countries, 46% of strains had a mutation in codon 315 of katG (katG315), and in a further 12%, mutations associated with the inhA gene, particularly in the promoter region, were found (Hazbón et al., 2006). Mutations in katG typically correlate with high-level resistance and inhA mutations with low-level resistance (Stoeckle et al., 1993; Cockerill et al., 1995; Ferrazoli et al., 1995; Morris et al., 1995; Rouse et al., 1995). Multiple mutations in other genes [alkyl hydroperoxide reductase (ahpC), NADH dehydrogenase (ndh), and ketoacyl synthase (kasA)] have been found in isoniazid-resistant M. tuberculosis isolates; however, mutations in these genes also occur in isoniazid-sensitive M. tuberculosis isolates, and only ahpC promoter mutations correlated well with isoniazid resistance (Hazbón et al., 2006).
Coordinated interaction between Lon protease and catalase-peroxidase regulates virulence and oxidative stress management during Salmonellosis
Published in Gut Microbes, 2022
Perumalraja Kirthika, Vijayakumar Jawalagatti, Amal Senevirathne, John Hwa Lee
The expression of katG in ST strains was confirmed by western blot analysis. Strains were grown to 0.6 OD at OD600. Four-milliliter cell samples were adjusted to have the same concentration (1 × 108 cells/ml), and all cells were collected by centrifugation. Cells were washed with PBS once and suspended in 0.5 ml of PBS. Cell lysis was carried out under denatured conditions using 8 M urea and brief sonication. The whole-cell lysate was filtered, and 20 µl of lysate was resolved in 12% SDS PAGE and transferred to a polyvinylidene difluoride membrane. Membranes were blocked with 5% BSA and incubated with anti-KatG polyclonal antibodies at 1:500 dilution. After two hours of incubation at 37°C, membranes were washed four times with 0.01% PBS-T and incubated with HRP-tagged anti-rabbit IgG as the secondary antibody (Southern Biotech, USA). Color development was achieved by adding 3, 3’-diaminobenzidine (DAB; Sigma Aldrich, USA) substrate.
Pharmacokinetics and other risk factors for kanamycin-induced hearing loss in patients with multi-drug resistant tuberculosis
Published in International Journal of Audiology, 2020
Nazanin Ghafari, Richard Court, Maxwell Tawanda Chirehwa, Lubbe Wiesner, Lucretia Petersen, Gary Maartens, Tawanda Gumbo, Helen McIlleron, Lebogang Ramma
We performed a prospective observational cohort study in adult patients on treatment for pulmonary MDR-TB at two TB hospitals in Cape Town: Brooklyn Chest Hospital and DP Marais Hospital. We enrolled patients 18 years of age or older initiated on therapy for MDR-TB within the previous month and explored the relationship between covariates including kanamycin exposure with hearing loss. Patients with middle ear pathology were excluded from the hearing analysis. During the study period, the standard regimen for MDR-TB consisted of pyrazinamide, moxifloxacin, kanamycin, terizidone and either ethionamide or isoniazid (depending on the presence of katG and inhA mutations identified by line-probe assay in the pre-treatment sputum culture, indicating high-level resistance to isoniazid or low-level resistance to isoniazid and resistance to ethionamide, respectively) (Caminero et al. 2010). Ethambutol was added if the risk of ethambutol resistance was considered to be low. Kanamycin was dosed intramuscularly daily, 6 times per week at 15 mg/kg per dose according to the South African Department of Health guidelines during the study period (South African Department of Health 2013), and adjusted for renal dysfunction at the discretion of the treating clinician. We assessed renal function at 4, 8 and 12 weeks post-treatment initiation, using the Cockroft-Gault method to calculate creatinine clearance.
Molecular identification of mutations conferring resistance to rifampin, isoniazid and pyrazinamide among Mycobacterium tuberculosis isolates from Iran
Published in Journal of Chemotherapy, 2020
Ahad Ali Haratiasl, Gholamreza Hamzelou, Sirus Amini, Jalil Kardan-Yamchi, Mehri Haeili, Fereshteh Heidari, Mohammad Mehdi Feizabadi
Resistance to isoniazid is linked to mutations in several genes, including katG, ahpC, and its promoter, and inhA promoter. In the previous studies, the most frequent mutation in INH-R isolates was related to katG (75%-90% mutations in codon 315, and 10% to 25% in other katG loci), followed by inhA (0%-5% mutations in ORF and 8% to 20% in the inhA promoter), ahpC and its promoter (6%-13%). Moreover, 10% to 25% of INH-R strains, lacked any mutations in these genes.26 In search of INH-resistance conferring mutations in the current work we found that 81.8% of INH-R isolates (n = 27 isolates) harbored mutations at codon 315 of katG, oxyR-ahpC intergenic region and inhA promoter region) 42.4%, 9.1% and 33.3% respectively). In 3 RIF-R and 6 INH-R isolates no mutations were observed in the studied loci, indicating that mutations in other loci not studied here or other mechanisms of resistance such as efflux pumps could have played a role in occurrence of resistance in these isolates. 27,28