Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin

Abstract

Terreic acid is a metabolite with antibiotic properties produced by the fungus Aspergillus terreus, but its cellular target remains unknown. We recently reported that terreic acid inactivates the bacterial cell wall biosynthetic enzyme MurA in vitro by covalent reaction with residue Cys115 in a similar manner as the MurA-specific antibiotic fosfomycin. To address if terreic acid also targets MurA in vivo, we conducted antibacterial studies using selected E. coli strains in parallel with fosfomycin. While overexpression of MurA conferred resistance to fosfomycin, it did not protect cells treated with terreic acid. Furthermore, flow cytometry revealed that the antibiotic action of terreic acid appears to be primarily bacteriostatic, as opposed to the bactericidal action observed for fosfomycin. Combined, the data suggest that MurA is not the molecular target of terreic acid and that the antibiotic activity of terreic acid proceeds through a different mechanism of action. The methodology applied here provides a reliable and convenient tool to rapidly assess the potential of newly discovered in vitro inhibitors to target residue Cys115 of MurA in the cell.

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

“…A small molecule inhibitor of MurG that augments the activity of β-lactams against methicillin-resistant Staphylococcus aureus was recently identified (141). MurA has been a popular target for the design of novel antibiotics, and several inhibitors of MurA have been identified that are active against various bacterial species (87,(142)(143)(144)(145)(146)(147). The chokepoint enzyme glucose-1-phosphate thymidylyltransferase (rfbA/rmlA), involved in O antigen biosynthesis, is also a target in Streptococcus pneumoniae (148) and Pseudomonas aeruginosa (149).…”

Molecular Mechanisms and Epidemiology of Fosfomycin Resistance in Staphylococcus aureus Isolated From Patients at a Teaching Hospital in China

“…Although several studies have mentioned that the overexpression of the murA gene can greatly increase the MICs of fosfomycin, the difference in murA expression between fosfomycin-sensitive and fosfomycin-resistant S. aureus has not been reported ( Garcia et al, 1995 ; Olesen et al, 2014 ). In the current study, the results of qRT-PCR revealed a significant difference between the fosfomycin-resistant and fosfomycin-susceptible S. aureus with respect to the expression of murA as compared with that of S. aureus ATCC 29213.…”

Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice

“…Terreic acid (catalog number SML0480, Sigma-Aldrich, St. Louis, MO, USA) was dissolved in saline and administered intraperitoneally at doses of 0, 3.75, 5, 7.5, or 15 mg/kg. These doses have been shown to have anti-inflammatory, antimicrobial, and anti-tumor actions (Han et al, 2010;Kawakami et al, 1999;Kawakami et al, 2007;Olesen et al, 2014;Yamamoto et al, 1980). Pergolide mesylate salt (catalog number P8828, Sigma-Aldrich) was dissolved in saline and administered intraperitoneally at doses of 0, 1, 2, or 4 mg/kg.…”