Abstract
Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent anti-tubercular regimens can lead to the anticipated non-compliance of the patient and increased drug toxicity, which in turn can contribute to the emergence of drug-resistant MTB strains that are not susceptible to first- and second-line available drugs. Hence, there is an urgent need for innovative antitubercular drugs and vaccines. A number of biochemical processes are required to maintain the correct homeostasis of DNA metabolism in all organisms. Here we focused on reviewing our current knowledge and understanding of biochemical and structural aspects of relevance for drug discovery, for some such processes in MTB, and particularly DNA synthesis, synthesis of its nucleotide precursors, and processes that guarantee DNA integrity and genome stability. Overall, the area of drug discovery in DNA metabolism appears very much alive, rich of investigations and promising with respect to new antitubercular drug candidates. However, the complexity of molecular events that occur in DNA metabolic processes requires an accurate characterization of mechanistic details in order to avoid major flaws, and therefore the failure, of drug discovery approaches targeting genome integrity.
Highlights
According to the most recent Global Tuberculosis Report (2019) edited by the World HealthOrganization (WHO), 10 million new Tuberculosis (TB) cases worldwide were estimated in 2018; there were 1.2 million TB deaths amongst HIV-negative patients, and an additional 250,000 deaths amongst HIV-positive patients [1]
The fifth step in the pathway, which is catalyzed by orotate phosphoribosyltransfrase (OPRT) [46,47]—a type I PRTase that converts orotate to orotidine 50 -monophosphate (OMP)—has been investigated as a potential drug target, and submicromolar pyrimidin-2(1H)-one-based inhibitors of the MTB OPRT enzyme have been identified, but as yet have not been tested on MTB to evaluate antibacterial activity [48]
It is common to refer to the Escherichia coli model when considering the overall process of DNA replication in MTB, it is important to note that some notable differences among these species have been described, including the observation that MTB lacks clear homologs of several initiation proteins (DnaC, DnaT, PriB and PriC) [55]
Summary
According to the most recent Global Tuberculosis Report (2019) edited by the World Health. Despite its central role in cell development and function, a limited number of approved TB drugs target DNA metabolism, which includes all the reactions involved in DNA replication and repair. These have been limited exclusively to the fluoroquinolones that interfere with DNA gyrase and DNA topoisomerase activity, and are frequently used as second-line drugs for the treatment of MDR-TB. Particular emphasis will be placed on recent results concerning the phenotypic screenings and biochemical characterization of macromolecular complexes acting in DNA metabolic pathways, as well as the innovative strategies that have been proposed to interfere with the formation of such complexes as potential sources of new targets for TB drug development
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