Nonselective Mevalonate Kinase Inhibitor as a Novel Class of Antibacterial Agents

Abstract

Introduction. There are a few evidences about targeting isoprenoids biosynthesis pathway in bacteria for finding new antibiotics. This study was conducted to assess antibacterial effects of vanadyl sulfate (VS), one of the mevalonate kinase inhibitors to find a new target for killing bacteria. Materials and Methods. Antibacterial effect of VS alone and in combination with glycine or EDTA was assessed on Escherichia coli and Pseudomonas aeruginosa as Gram-negative and Staphylococcus aureus and Enterococcus faecalis as Gram-positive bacteria using serial dilution method and minimum inhibitory concentrations (MICs) identified. Result. MICs for S. aureus and E. coli were 4 and 8 mg/mL, respectively. VS could not affect the growth of two other bacteria. However, VS in combination with glycine not only inhibited the growth of E. faecalis and P. aeruginosa, but also reduced MICs for VS-sensitive bacteria (S. aureus and E. coli). EDTA could reduce MIC for E. coli and P. aeruginosa. Conclusion. VS could inhibit the growth of S. aurous and E. coli, and adding glycine or EDTA improved VS antibacterial activity presumably via instability of the cell wall and enhanced transport of VS through bacterial cell wall. Inhibition of the isoprenoid pathway might provide new tools to overcome bacterial resistance.

Characterization of feedback-resistant mevalonate kinases from the methanogenic archaeons Methanosaeta concilii and Methanocella paludicola

“…Further study of archaeal MVKs and their comparison with bacterial and eukaryotic enzymes can provide new insights into the mechanism of interaction between potential inhibitors and prokaryotic and eukaryotic MVKs. Such an investigation would provide interesting ideas for the relief of MVK inhibition in patients with autoinflammatory disorders caused by a mevalonate kinase (MK) deficiency [ 48 ] and for the design of new MVK inhibitors, which are being considered as potential drugs for the treatment of cardiovascular diseases and cancer [ 49 ] and as antibacterial agents [ 50 ].…”

Harnessing cGAS–STING axis for therapeutic benefits in systemic lupus erythematosus

“…25,26 cGAS responses in a variety of infectious and hereditary diseases, such as amyotrophic lateral sclerosis (ALS) and coronavirus disease 2019 (COVID- 19), have been associated with mtDNA failure. [27][28][29] Furthermore, it has been shown that cGAS is activated by neutrophil extracellular traps (NETs), which are rich in extracellular genomic DNA. 30 HeLa cells and primary human monocytes were demonstrated to produce IFN-I as a result of genomic DNA damage, suggesting a connection between DNA damage and the self-initiated innate immune response.…”

“…In the case of mitochondrial failure, the mitochondrial DNA (mtDNA), which is a rich reservoir of extranuclear self‐DNA, might leak out into the cytoplasm 25,26 . cGAS responses in a variety of infectious and hereditary diseases, such as amyotrophic lateral sclerosis (ALS) and coronavirus disease 2019 (COVID‐19), have been associated with mtDNA failure 27–29 . Furthermore, it has been shown that cGAS is activated by neutrophil extracellular traps (NETs), which are rich in extracellular genomic DNA 30 .…”

Diabetes and diabesity in the view of proteomics, drug, and plant-derived remedies

“…[ 99 ] The binding of vanadium to organic compounds (such as glycine and EDTA) facilitates its passage through bacterial membranes and increases its effectiveness. [ 132 ] Furthermore, an organic vanadium complex (Bis [α-furancarboxylato] oxovanadium [IV]) increases insulin sensitivity, and GK activity, and inhibits PEPCK, a key enzyme in gluconeogenesis. These effects may be exerted, at least in part, by nonselective inhibition of phosphotyrosine phosphatase.…”