Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis (original) (raw)
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DRUG RESISTANCE OF MYCOBACTERIUM TUBERCULOSIS TO RIFAMPICIN AND ISONIAZID: A MOLECULAR APPROACH
uberculosis (TB) is one of the important re-emerging infectiousdiseases. Due to its infectious nature, one third of the world'spopulation is latently infected with the causative agent Mycobacteriumtuberculosis and annual new cases of TB worldwide countsapproximately 9 million. This disease is associated with moredeaths than any other single infectious agents.The increasing emergence of multidrug-resistant tuberculosis (MDR-TB) in the era of HIV infection presents a major threat to effective control of tuberculosis. The Centers for Disease Control (CDC) defines MDR-TB as TB infectionthat is resistant to multiple anti-TB medications, includingat least two of the first line agents used to treat TB (isoniazidand rifampicin). Drug resistance in Mycobacteriumtuberculosis arises from spontaneous chromosomal mutations at low frequency. Clinical drug-resistant TB largely occurs as a result of man-made selection during disease treatment of these genetic alterations through erratic drug supply, suboptimal physician prescription and poor patient adherence. The relationship between drug resistance in M. tuberculosis strains and their virulence needs to be further investigated. Understanding the mechanisms of drug resistance in M. tuberculosis would enable the development of rapid molecular diagnostic tools and furnish possible insights into new drug development for the treatment of TB.
2020
Drug-resistant TB (TB) is a serious global problem, not only complicates the treatment of patients with resistant strains of TB, but also poses a threat to the global process to achieve the goals of the TB elimination strategy in the world by the World Health Organization (WHO) [1]. WHO estimates that 1.674 million people died of tuberculosis in 2016 alone, while between 2000 and 2016 they were healed 52.5 million lives thanks to improved diagnosis and treatment. At the same time, 13 of the 22 highest burden countries failed to meet the target for the decline in tuberculosis prevalence in 2014, highlighting the need to improve strategies to combat the disease [2]. Effective TB control is especially challenging among patients with multidrug-resistant TB (MDR-TB), which are resistant to at least isoniazid and rifampicin, the two most potent anti-TB drugs used in standard first-line treatment. For example, 2015 data show that by the end of 2014, 153 countries had reported the circulati...
Current Approaches to Control of Isoniazid-Resistant Tuberculosis
PROBLEMS of Infectious and Parasitic Diseases
Isoniazid (H; INH) is an important first-line drug for the treatment of active tuberculosis (TB) and latent TB infection because of its potent early bactericidal activity against Мycobacterium tuberculosis. Currently, TB resistant to INH, alone or in combination with other drugs, is the most common type of drug-resistant TB. Epidemiology of INH-resistant TB, the molecular mechanisms of drug resistance, current methods for diagnosis and therapeutic regimens of this TB form are presented. Studies in the last years have shown that resistance to INH reduces the probability of treatment success and increases the risk of acquiring resistance to other important first-line drugs. Based on the most recent meta-analyses, the last WHO recommendations for treatment of INH-resistant TB are to include rifampicin (RIF), ethambutol, pyrazinamide and levofloxacin for 6 months, and not to add streptomycin or other injectable agents to the drug regimen. The guideline emphasizes the importance of excl...
Mutation as a Molecular Determinant for Isoniazid Resistance in Mycobacterium tuberculosis
2017
Emergence of multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) is one of the reasons why tuberculosis (TB) continues to cause great mortality and morbidity in less-developed countries. The development of rapid diagnostic methods targeting genetic mutations associated with resistance to the anti-tuberculous drugs is essential to fight this deadly pathogen. Isoniazid (INH) has been included in the multidrug regimens for the treatment of drug-susceptible TB for the decades. In the worldwide setting, isoniazid resistance was highly prevalent and was observed in one of every seven TB cases. Since katG315 mutation is highly prevalent, the common mutation in the enzyme essential for the activation of the INH concerned with the mechanism of drug resistance and associated with high level resistance to INH, katG315 mutation was necessary to be identified by molecular method as a molecular determinant of INH resistant Mycobacterium tuberculosis. The...
The International Journal of Tuberculosis and Lung Disease, 2012
Based on data from 14 Supranational Tuberculosis (TB) Reference Laboratories worldwide, the proportion of rifampicin-resistant isolates that were isoniazid-susceptible by phenotypic drugsusceptibility tests varied widely (0.5%-11.6%). Rifampicin-resistant isolates that were isoniazidsusceptible had significantly lower rates of resistance to other first-line and second-line anti-TB drugs (except rifabutin) compared to multidrug-resistant isolates. Rifampicin resistance is not always a good proxy for a presumptive diagnosis of multidrug-resistant tuberculosis, which has implications for use of molecular assays that identify only rifampicin resistance-associated DNA mutations.
Antitubercular Isoniazid and Drug Resistance of Mycobacterium tuberculosis — A Review
Archiv Der Pharmazie, 2002
Isoniazid is one of the most potent drugs available for tuberculosis treatment. As a pro-drug it requires activation, which is performed by catalase/peroxidase. The active principle, whose identity has not yet been determined unambiguously, then acts on at least one target molecule, the enoyl-acyl carrier protein, required for the synthesis of the vital mycolic acids present in the cell wall of the bacterium. Some other targets have been proposed in order to explain the unusual potency of isoniazid; however, the supporting data are still controversial. We thoroughly discuss the action of isoniazid, resistance mechanisms, and the possible active product, which includes an isonicotinic acid-NADH adduct as well as a meta-isomer of NADH. Both structures have been probed positively in a 3D modeling analysis.
Journal of Antimicrobial Chemotherapy, 2011
Tuberculosis (TB) remains one of the leading public health problems worldwide. Declared as a global emergency in 1993 by the WHO, its control is hampered by the emergence of multidrug resistance (MDR), defined as resistance to at least rifampicin and isoniazid, two key drugs in the treatment of the disease. More recently, severe forms of drug resistance such as extensively drug-resistant (XDR) TB have been described. After the discovery of several drugs with anti-TB activity, multidrug therapy became fundamental for control of the disease. Major advances in molecular biology and the availability of new information generated after sequencing the genome of Mycobacterium tuberculosis increased our knowledge of the mechanisms of resistance to the main anti-TB drugs. Better knowledge of the mechanisms of drug resistance in TB and the molecular mechanisms involved will help us to improve current techniques for rapid detection and will also stimulate the exploration of new targets for drug activity and drug development. This article presents an updated review of the mechanisms and molecular basis of drug resistance in M. tuberculosis. It also comments on the several gaps in our current knowledge of the molecular mechanisms of drug resistance to the main classical and new anti-TB drugs and briefly discusses some implications of the development of drug resistance and fitness, transmission and pathogenicity of M. tuberculosis.