Abstract
Isoniazid (INH) is one of the most commonly used drugs in treatment of human tuberculosis and the most efficient. Although it has been 60 years since isoniazid was introduced in anti-tubercular therapy and despite the simplicity of its chemical structure (C6H7N3O) with few functional groups, its exact mechanism of action, which could account for its specificity and exceptional potency against Mycobacterium tuberculosis and justify all profiles of INH-resistance, remains elusive and debatable. This complexity can find an explanation in the high reactivity of INH and also in the possibility that multiple targets and pathways could co-exist for this medicinal agent. Indeed, since the discovery of isoniazid’s anti-tubercular potency, several propositions for its mode of action have been reported, including its conversion, by a catalase peroxidase within M. tuberculosis, into an active metabolite able, after reaction with NAD, to inhibit an enzyme (InhA) crucial to M. tuberculosis survival. This represents the most consensual mechanism described to date. Nevertheless, none of the proposed mechanisms considered independently can explain the singular and privileged action of the isoniazid structure on the tubercle bacillus, or all the profiles of resistance. The aim of this paper is to reconsider the literature reporting the different modes of action described for isoniazid in the light of the present and most relevant knowledge, with special attention to understanding the molecular mechanistic aspects of the drug’s action.
Keywords: Isoniazid, KatG, mechanism of action, Mycobacterium tuberculosis, pro-drug, radicals, isoniazid resistances.
Current Medicinal Chemistry
Title:Isoniazid: an Update on the Multiple Mechanisms for a Singular Action
Volume: 20 Issue: 35
Author(s): V. Bernardes-Génisson, C. Deraeve, A. Chollet, J. Bernadou and G. Pratviel
Affiliation:
Keywords: Isoniazid, KatG, mechanism of action, Mycobacterium tuberculosis, pro-drug, radicals, isoniazid resistances.
Abstract: Isoniazid (INH) is one of the most commonly used drugs in treatment of human tuberculosis and the most efficient. Although it has been 60 years since isoniazid was introduced in anti-tubercular therapy and despite the simplicity of its chemical structure (C6H7N3O) with few functional groups, its exact mechanism of action, which could account for its specificity and exceptional potency against Mycobacterium tuberculosis and justify all profiles of INH-resistance, remains elusive and debatable. This complexity can find an explanation in the high reactivity of INH and also in the possibility that multiple targets and pathways could co-exist for this medicinal agent. Indeed, since the discovery of isoniazid’s anti-tubercular potency, several propositions for its mode of action have been reported, including its conversion, by a catalase peroxidase within M. tuberculosis, into an active metabolite able, after reaction with NAD, to inhibit an enzyme (InhA) crucial to M. tuberculosis survival. This represents the most consensual mechanism described to date. Nevertheless, none of the proposed mechanisms considered independently can explain the singular and privileged action of the isoniazid structure on the tubercle bacillus, or all the profiles of resistance. The aim of this paper is to reconsider the literature reporting the different modes of action described for isoniazid in the light of the present and most relevant knowledge, with special attention to understanding the molecular mechanistic aspects of the drug’s action.
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Bernardes-Génisson V., Deraeve C., Chollet A., Bernadou J. and Pratviel G., Isoniazid: an Update on the Multiple Mechanisms for a Singular Action , Current Medicinal Chemistry 2013; 20 (35) . https://dx.doi.org/10.2174/15672050113109990203
DOI https://dx.doi.org/10.2174/15672050113109990203 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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