Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

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.

Elucidating the Antimycobacterial Mechanism of Action of Ciprofloxacin Using Metabolomics

“…Various PPP intermediates that contribute to DNA and cell wall synthesis were detected to be altered in the ciprofloxacin-treated Mtb, [99,108,109]. Under normal circumstances, erythrose-4-phosphate and glyceraldehyde-3-phosphate produce xylulose-5-phosphate (xylulose-5P) and fructose-6-phosphate (fructose-6P) [91].…”

Elucidating the antimycobacterial mechanism of action of ciprofloxacin using metabolomics

“…Various PPP intermediates were detected to be altered in the ciprofloxacin treated Mtb, which contribute to DNA and cell wall repair [94,102,103]. Under normal circumstances, erythrose-4-phosphate and glyceraldehyde-3-phosphate produce xylulose-5-phosphate (xylulose-5P) and fructose-6-phosphate (fructose-6P) [91].…”

Prebiotic Chemistry: The Role of Trimetaphosphate in Prebiotic Chemical Evolution

“…Nucleotides are the fundamental building units of RNA and DNA, the two polymers responsible for life’s biochemistry ( Azzam and Liu, 2013 ; Shivakumar et al, 2019 ; Miggiano et al, 2020 ; Cai et al, 2021 ). The investigation of their synthesis has made a substantial contribution to our understanding of chemical evolution and the chemical origins of life.…”