Antibacterial Activity of REP8839, a New Antibiotic for Topical Use

Abstract

REP8839 is a novel methionyl-tRNA synthetase (MetS) inhibitor with potent antibacterial activity against clinical isolates of Staphylococcus aureus, Streptococcus pyogenes, and other clinically important gram-positive bacteria but little activity against gram-negative bacteria. All isolates of S. aureus, including strains resistant to methicillin, mupirocin, vancomycin, and linezolid were susceptible to REP8839 at concentrations of <0.5 g/ml. REP8839 was also active against Staphylococcus epidermidis, including multiply resistant strains (MIC, <0.25 g/ml). All S. pyogenes isolates were susceptible to REP8839 at concentrations of <0.25 g/ml, suggesting that MetS2, a second enzyme previously identified in Streptococcus pneumoniae, was not present in this organism. REP8839 was highly bound to the protein of human serum, and activity was not greatly influenced by inoculum size but was affected by pH, exhibiting optimal antibacterial activity in a neutral medium rather than a weak acidic medium. Like mupirocin, REP8839 exhibited bacteriostatic activity against key pathogens. The emergence of mupirocin resistance in S. aureus highlights the need for a new topical antibiotic with the ability to inhibit high-level mupirocin-resistant strains and other emerging phenotypes, such as vancomycinresistant and community-acquired methicillin-resistant isolates.

Discovery of a Novel Class of Boron-Based Antibacterials with Activity against Gram-Negative Bacteria

“…Unless stated otherwise, compound, E. coli LeuRS (22), and E. coli total tRNA (Roche) were preincubated for 20 min in 50 mM HEPES-KOH (pH 8.0), 30 LeuRS reactivation rate determination. To establish the reversibility of inhibition, 40 nM E. coli LeuRS and sufficient tRNA and compound were preincubated for 1 h at 4°C to inhibit 90% of the enzyme's activity (ϳ10ϫ 50% inhibitory concentration [IC 50 ]).…”

“…Kinetics of in vitro activity. Aminoacyl-tRNA synthetase inhibitors are bacteriostatic agents (30); thus, the bacteriostatic activity of AN3365 with E. coli ATCC 25922 was to be expected (Fig. 5A).…”

“…All previous AARS inhibitors are bacteriostatic agents (30,31) and they inhibit AARS enzymes by binding to the synthetic active site, whereas the aminomethylbenzoxaboroles block tRNA aminoacylation by trapping the tRNA in the editing conformation. Since the levels of the respective AARS and their cognate tRNA are tightly regulated to avoid mischarging (32), it is plausible that the sequestration of tRNA Leu on LeuRS might generate a different response to that observed with previous AARS inhibitors.…”

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

“…REP3123 and REP8839 are known inhibitors of bacterial MRSs and show potent and selective activity, with minimal cytotoxicity for mammalian cells (43 activity with a K i of 10 pM against Staphylococcus aureus (23,24). Therefore, we tested the effects of these MRS inhibitors on malaria parasite growth in vitro.…”

Evaluation of the metS and murB Loci for Antibiotic Discovery Using Targeted Antisense RNA Expression Analysis in Bacillus anthracis

“…MetS provides a logical and potent alternative inhibition point in protein synthesis, as the resulting charged methionyl-tRNA is used both for translation initiation and elongation by the bacterial ribosome. Several classes of MetS inhibitors with antibacterial activity have been reported (12,19,25,30), including one that is in preclinical development (12,45). The MurB enzyme, UDP-N-acetylenolpyruvoylglucosamine reductase, catalyzes an early and crucial step in the cell wall biosynthesis pathway.…”