Abstract
Worldwide, tuberculosis is the leading cause of morbidity and mortality due to a single bacterial pathogen, Mycobacterium tuberculosis (Mtb). The increasing prevalence of this disease, the emergence of multi-, extensively, and totally drug-resistant strains, complicated by co-infection with the human immunodeficiency virus, and the length of tuberculosis chemotherapy have led to an urgent and continued need for the development of new and more effective antitubercular drugs. Within this context, the L-histidine biosynthetic pathway, which converts 5-phosphoribosyl 1-pyrophosphate to L-histidine in ten enzymatic steps, has been reported as a promising target of antimicrobial agents. This pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants but is absent in mammals, making these enzymes highly attractive targets for the drug design of new antimycobacterial compounds with selective toxicity. Moreover, the biosynthesis of L-histidine has been described as essential for Mtb growth in vitro. Accordingly, a comprehensive overview of Mycobacterium tuberculosis histidine pathway enzymes as attractive targets for the development of new antimycobacterial agents is provided, mainly summarizing the previously reported inhibition data for Mtb or orthologous proteins.
Keywords: Drug design, enzymatic inhibitors, antimycobacterial, L-histidine biosynthesis, molecular target, Mycobacterium tuberculosis.
Current Topics in Medicinal Chemistry
Title:Targeting the Histidine Pathway in Mycobacterium tuberculosis
Volume: 13 Issue: 22
Author(s): Juleane Lunardi, José Eduardo S. Nunes, Cristiano V. Bizarro, Luiz Augusto Basso, Diógenes Santiago Santos and Pablo Machado
Affiliation:
Keywords: Drug design, enzymatic inhibitors, antimycobacterial, L-histidine biosynthesis, molecular target, Mycobacterium tuberculosis.
Abstract: Worldwide, tuberculosis is the leading cause of morbidity and mortality due to a single bacterial pathogen, Mycobacterium tuberculosis (Mtb). The increasing prevalence of this disease, the emergence of multi-, extensively, and totally drug-resistant strains, complicated by co-infection with the human immunodeficiency virus, and the length of tuberculosis chemotherapy have led to an urgent and continued need for the development of new and more effective antitubercular drugs. Within this context, the L-histidine biosynthetic pathway, which converts 5-phosphoribosyl 1-pyrophosphate to L-histidine in ten enzymatic steps, has been reported as a promising target of antimicrobial agents. This pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants but is absent in mammals, making these enzymes highly attractive targets for the drug design of new antimycobacterial compounds with selective toxicity. Moreover, the biosynthesis of L-histidine has been described as essential for Mtb growth in vitro. Accordingly, a comprehensive overview of Mycobacterium tuberculosis histidine pathway enzymes as attractive targets for the development of new antimycobacterial agents is provided, mainly summarizing the previously reported inhibition data for Mtb or orthologous proteins.
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Lunardi Juleane, Nunes Eduardo S. José, Bizarro V. Cristiano, Basso Augusto Luiz, Santos Santiago Diógenes and Machado Pablo, Targeting the Histidine Pathway in Mycobacterium tuberculosis, Current Topics in Medicinal Chemistry 2013; 13 (22) . https://dx.doi.org/10.2174/15680266113136660203
DOI https://dx.doi.org/10.2174/15680266113136660203 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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