Food for thought: Opportunities to target carbon metabolism in antibacterial drug discovery

Abstract

Antimicrobial resistance is at an all‐time high and new drugs are required to overcome this crisis. Traditional approaches to drug discovery have failed to produce novel classes of antibiotics, with only a few currently in development. It is thought that novel classes will come from antibacterial drug discovery efforts that focus on unconventional targets. One such collection of antibacterial targets are those that comprise central carbon metabolism. Targets of this kind have been largely overlooked because conventional antibacterial testing media are ill‐suited for exploring carbon source utilization. Nevertheless, as a consequence of infection, bacteria must find a carbon source in order to survive. Here, we review what is known about the carbon sources available and used by bacteria in different host infection sites. We also look at discovery efforts targeting central carbon metabolism and evaluate how these processes can influence antibiotic efficacy.

Antibacterial Activities of the Algal Bromophenol Methylrhodomelol Against Pseudomonas aeruginosa

“…Also, expression of oxidase Aa3 was not induced by any other stressor 42 , and the available carbon source was shown to have a major influence on the respiratory chain 43 . These findings suggest that the growth defect observed in minimal medium could be caused by nutrient starvation due to interference with the carbon metabolism 44 . Upregulation of branched-chain (ACG06_RS16385–ACG06_RS16400; liuABCR ) and aromatic amino acid (ACG06_RS16420; hmgA, hppD ) catabolism, which represent non-preferential carbon sources 45 , 46 , further support the hypothesis of methylrhodomelol interfering with carbon metabolism.…”

“…The limited amount of substance available of this minor compound from V. lanosa did not allow further evaluation of its antimicrobial and resistance-modulating activity. But, due to the increasing evidence of energy and carbon metabolism being connected to bacterial virulence and antibiotic resistance [44], a broader exploration of the antimicrobial properties of methylrhodomelol, including other bacterial species, a variation of assay media, and extended testing in combination with standard antibiotics, could be an interesting topic of further research.…”

Providing insight into the mechanism of action of cationic lipidated oligomers using metabolomics

“…This process provides precursors for all the biosynthetic reactions that are required for cell survival ( 63 , 64 ). This makes central carbon metabolism, i.e., carbon uptake and carbon utilization, an attractive antimicrobial target because these processes are typically essential for microbial survival ( 65 – 67 ). Innate immunity, which frequently deprives bacteria of iron, amino acids, and other essential nutrients, serves as an example of the efficacy of this strategy ( 68 – 70 ).…”

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. ,− …”

“…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. 1 − 3 Agents that target central metabolic processes are increasingly sought 4 − 15 and have the potential to exert narrow-spectrum activities. 4 , 16 − 19 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.…”