Isoniazid

Isoniazid is an antibacterial agent used primarily as a tuberculostatic. Target: Antibacterial Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG [1]. KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide, which has also been shown to be important in the action of another antimycobacterial prodrug PA-824 [2, 3]. Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing [4].

References:
[1]. Suarez, J., et al., An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG). J Biol Chem, 2009. 284(11): p. 7017-29. [2]. Timmins, G.S., et al., Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2004. 48(8): p. 3006-9. [3]. Singh, R., et al., PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science, 2008. 322(5906): p. 1392-5. [4]. Ahmad, Z., et al., Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig. J Infect Dis, 2009. 200(7): p. 1136-43.

Inflammatory bowel disease and mycobacteria: how much can we trust isoniazid prophylaxis during antitumor necrosis factor therapy?[Pubmed:30964811]

Eur J Gastroenterol Hepatol. 2019 Apr 5.

OBJECTIVES: Isoniazid (INH) prophylaxis is recommended for the prevention of tuberculosis (TB) reactivation before or/and during initiation of treatment with tumour necrosis factor antagonists (anti-TNF agents). Nonetheless, the long-term effectiveness of chemoprophylaxis is not clear. In this study, we aimed to evaluate the characteristics of patients who developed TB reactivation in spite of INH prophylaxis associated with anti-TNF treatment. PATIENTS AND METHODS: In this retrospective study, medical records of 1263 patients with inflammatory bowel disease were reviewed. Baseline TB screening tests (purified protein derivative test and/or QuantiFERON-TB Gold test) were performed on all patients before initiation of anti-TNF therapy. Patients with purified protein derivative of more than 5 mm and/or a positive result of the QuantiFERON-TB Gold test received INH prophylaxis for 9 months. We analysed the data of patients diagnosed with TB reactivation during the anti-TNF treatment despite INH chemoprophylaxis. RESULTS: Overall, 175 patients underwent anti-TNF treatment. Sixty of these 175 patients had pretreatment testing showing latent TB infection and therefore were treated concomitantly with INH for 9 months in addition to their anti-TNF treatment. TB reactivation occurred in four of these 60 co-INH/anti-TNF treated patients. Active TB was diagnosed after 37.5+/-27 (range: 18-84) months of anti-TNF treatment. In two of the four patients that active TB was diagnosed, was also detected other Mycobacterium spp.: M. bovis in one patient and M. genavense in the other one. CONCLUSION: INH chemoprophylaxis may not prevent the reactivation of TB during anti-TNF therapy in the long-term. Patients should be carefully and periodically screened for TB reactivation during anti-TNF therapy.

Seizures following Intoxication with a Common Antituberculosis Drug.[Pubmed:30956835]

Case Rep Pediatr. 2019 Mar 5;2019:8972574.

Isoniazid is an antimycobacterial agent commonly prescribed in most tuberculosis chemotherapy regimens. Its side effects are widely known including mainly liver toxicity and peripheral neuropathy. The toxic effects of Isoniazid are dose-related. Toxic doses are estimated at 35-40 mg/kg and fatal doses at 150 mg/kg. Treatment consists primarily of basic life support, antiepileptic drugs, and pyridoxine. The case is of one of the children with intentional Isoniazid poisoning, the drug belonging to an uncle currently under antituberculosis treatment, resulting in tonic-clonic seizures. During her hospitalization in the paediatric intensive care unit, her neurological status as well as her lab values was closely monitored, and despite initial deterioration, the patient was discharged from critical care a week after full recovery.

Mannopyranoside Glycolipids Inhibit Mycobacterial Growth, Biofilm and Potentiate Isoniazid Inhibition Activities in M. smegmatis.[Pubmed:30951240]

Chembiochem. 2019 Apr 5.

Lipomannan and lipoarabinomannan are integral components of mycobacterial cell wall. Our earlier studies demonstrated that synthetic arabinan and arabinomannan glycolipids act as inhibitors of mycobacterial growth, in addition to exhibiting inhibitory activities of mycobacterial biofilm. In the present study, we demonstrate that synthetic mannan glycolipids are better inhibitors of the mycobacterial growth, whereas, lipoarabinomannan has higher inhibition efficiencies to biofilm. Syntheses of mannan glycolipids with graded number of mannan moieties and an arabinomannan glycolipid are conducted by chemical methods and subsequent mycobacterial growth and biofilm inhibition studies are conducted on M. smegmatis. Growth inhibition of 73 +/- 3% is observed with a mannose trisaccharide containing glycolipid, whereas this glycolipid did not promote biofilm inhibition activity better than arabinomannan glycolipid. The antibiotic supplementation activities of glycolipids on growth and biofilm inhibitions are evaluated. Fold increases in the growth and biofilm inhibitions are observed when the antibiotic is supplemented with glycolipids, leading to a significant reduction of inhibition concentrations of the antibiotic.

JVA, an isoniazid analogue, is a bioactive compound against a clinical isolate of the Mycobacterium avium complex.[Pubmed:30948164]

Tuberculosis (Edinb). 2019 Mar;115:108-112.

Bacteria belonging to Mycobacterium avium complex are organisms of low pathogenicity that infect immunosuppressed individuals. Infection is treated with an antimicrobial macrolide, Clarithromycin (CAM) or Azitromycin, associated with Ethambutol and Rifabutin during 12 months. Regimen long duration and side effects hinder patient's commitment to treatment favoring emergence of antibiotic resistance. In this present study, we evaluated the activity of JVA, an Isoniazid (INH) derivative, against M. avium 2447, a clinical isolate. We demonstrated that JVA reduces M. avium 2447 growth in macrophages, more efficiently than CAM and INH. In order to explore JVA mechanism of action, we investigated compound properties and performed pH-dependent stability studies. Our results suggest an enhanced ability of JVA to cross biological membranes. Furthermore, we suggest that in acidic conditions of macrophages' phagosomes, where mycobacteria replicate, JVA would be promptly hydrolyzed to INH, delivering the adduct INH-nicotinamide adenine dinucleotide and thus inhibiting M. avium 2447 growth.

Mitochondrial Damage and Drp1 Overexpression in Rifampicin- and Isoniazid-induced Liver Injury Cell Model.[Pubmed:30944818]

J Clin Transl Hepatol. 2019 Mar 28;7(1):40-45.

Background and Aims: Rifampicin (RFP) and Isoniazid (INH) are widely used as anti-tuberculosis agents. However, the mechanisms underlying the involvement of reactive oxygen species and mitochondria in RFP- and INH-related hepatotoxicity have not been established yet. This study aimed to observe the intracellular mechanisms leading to mitochondrial dysfunction and morphological changes in RFP- and INH-induced hepatocyte injury. Methods: Cell injury, changes in mitochondrial function, and expression and activation of dynamin related protein 1 (Drp1), known as the main protein for mitochondrial fission, were analyzed in cultured QSG7701 cells exposed to RFP and INH. Results: INH and RFP treatment induced pronounced hepatocyte injury and increased cell death. In the similar context of aspartate aminotransferase elevation and adenosine triphosphate synthesis decrease, changes in mitochondrial membrane permeability and reactive oxygen species in hepatocytes induced by RFP were significantly different from those induced by INH (p < 0.05). Particularly, we observed the overactivation and mitochondrial translocation of Drp1 in RFP-induced cell injury, which was not occurred with exposure to INH. Conclusions: RFP-induced hepatotoxicity may be closely related to mitochondrial dysfunction and Drp1-mediated mitochondrial fission.

Whole genome sequencing identifies bacterial factors affecting transmission of multidrug-resistant tuberculosis in a high-prevalence setting.[Pubmed:30944370]

Sci Rep. 2019 Apr 3;9(1):5602.

Whole genome sequencing (WGS) can elucidate Mycobacterium tuberculosis (Mtb) transmission patterns but more data is needed to guide its use in high-burden settings. In a household-based TB transmissibility study in Peru, we identified a large MIRU-VNTR Mtb cluster (148 isolates) with a range of resistance phenotypes, and studied host and bacterial factors contributing to its spread. WGS was performed on 61 of the 148 isolates. We compared transmission link inference using epidemiological or genomic data and estimated the dates of emergence of the cluster and antimicrobial drug resistance (DR) acquisition events by generating a time-calibrated phylogeny. Using a set of 12,032 public Mtb genomes, we determined bacterial factors characterizing this cluster and under positive selection in other Mtb lineages. Four of the 61 isolates were distantly related and the remaining 57 isolates diverged ca. 1968 (95%HPD: 1945-1985). Isoniazid resistance arose once and rifampin resistance emerged subsequently at least three times. Emergence of other DR types occurred as recently as within the last year of sampling. We identified five cluster-defining SNPs potentially contributing to transmissibility. In conclusion, clusters (as defined by MIRU-VNTR typing) may be circulating for decades in a high-burden setting. WGS allows for an enhanced understanding of transmission, drug resistance, and bacterial fitness factors.