Implications of Mycobacterium tuberculosis Metabolic Adaptability on Drug Discovery and Development

Abstract

Tuberculosis remains a global health threat that is being exacerbated by the increase in infections attributed to drug resistant Mycobacterium tuberculosis. To combat this, there has been a surge in drug discovery programs to develop new, potent compounds and identify promising drug targets in the pathogen. Two areas of M. tuberculosis biology that have emerged as rich sources of potential novel drug targets are cell wall biosynthesis and energy metabolism. Both processes are important for survival of M. tuberculosis under replicating and nonreplicating conditions. However, both processes are also inherently adaptable under different conditions. Furthermore, cell wall biosynthesis is energy intensive and, thus, reliant on an efficiently functioning energy production system. This Perspective focuses on the interplay between cell wall biosynthesis and energy metabolism in M. tuberculosis, how adaptations in one pathway may affect the other, and what consequences this could have for drug discovery and development and the identification of novel drug targets.

Antibacterial Target DXP Synthase Catalyzes the Cleavage of d-Xylulose 5-Phosphate: a Study of Ketose Phosphate Binding and Ketol Transfer Reaction

“…1-Deoxy- d -xylulose 5-phosphate synthase (DXPS) is a thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the formation of DXP from pyruvate and d -glyceraldehyde 3-phosphate ( d -GAP) in bacteria, apicomplexan parasites, and plants. − Due to its importance to bacterial metabolism and absence from human metabolism, DXPS is a promising antibacterial drug target. − Its product, DXP, is a branch-point metabolite that feeds into three essential pathways for metabolite synthesis: ThDP, pyridoxal phosphate, and isoprenoid biosynthesis from isopentenyl diphosphate and dimethylallyl diphosphate (Figure ). , Bacterial pathogen metabolism rapidly changes in response to environmental conditions. − During infection, fluctuating host environments force bacteria to adapt through differential gene expression, metabolic regulation, and modulation of enzyme activity to ensure survival. − Given its role in essential cofactor and isoprenoid biosynthesis, we hypothesize that DXPS is critical for such bacterial adaptations.…”

Potent Inhibition of E. coli DXP Synthase by a gem-Diaryl Bisubstrate Analog

“…Antimicrobial resistance predates the discovery of antibiotics and is an unavoidable threat in the treatment of infectious diseases. To combat resistance, new antibacterial strategies are needed that are selective for pathogens and avoid toxicity to the host microbiome, which can negatively impact human health. − Agents that target central metabolic processes are increasingly sought − and have the potential to exert narrow-spectrum activities. ,− However, this target space is relatively underexploited owing to the complexities in developing central metabolism targets and the perceived difficulties in selectively targeting bacterial metabolism over host metabolism. ,,, Essential to bacterial central metabolism and absent in humans, 1-deoxy- d -xylulose 5-phosphate synthase (DXPS) emerged as a promising antibacterial target with the potential to offer opportunities for developing narrow spectrum approaches. ,− …”