Antibacterial Effect of Some Eukaryotic Sterol Biosynthesis Inhibitors.

Background: Isoprenoids and their derivatives are building blocks for the synthesis of biomolecules with important biological functions such as cholesterol in eukaryotes and lipid carrier undecaprenol, which is involved in cell wall biosynthesis in bacteria. With the global threat of multidrug-resistant bacteria, there is a need for finding new metabolic targets for killing bacteria. In the present study, we examined the impact of eukaryotic sterol biosynthesis inhibitors on the growth of four pathogenic bacteria. Materials and Methods: Antibacterial effect of HMG CoA reductase inhibitor (simvastatin), farnesyl pyrophosphate synthase inhibitor (alendronate), squalene epoxidase inhibitor (terbinafine), and lanosterol demethylase inhibitor (ketoconazole) were studied against four pathogenic bacteria: two gram-positive bacteria, Staphylococcus aureus and Enterococcus faecalis and two gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa. Broth microdilution method was used for assessing the antibacterial susceptibility of the components using 96 well plats. MIC and MBC were determined visibly. Results: MIC of Ketoconazole for Staphylococcus aureus and Enterococcus faecalis were 0.166 and 1 mg/mL, respectively. Terbinafine had a weak inhibitory effect on Staphylococcus aureus (MIC: 8 mg/mL). Ketoconazole and terbinafine had no inhibitory effect on gram-negative bacteria. MBC of Simvastatin for both Staphylococcus aureus and Enterococcus faecalis was 0.5 mg/mL and of Alendronate for Pseudomonas aeruginosa was 6.6 mg/mL. Conclusion: Our results show that farnesyl pyrophosphate synthase and class II HMG-CoA reductases inhibitors (ketoconazole and simvastatin) have reasonable antibacterial activity against gram-positive bacteria. These two enzymes provide suitable targets for designing new antibiotics based on modifying the chemical structure of currently used drugs to obtain maximum activity.

Nonselective mevalonate kinase inhibitor as a novel class of antibacterial agents.

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.