Critchley Ian A, Young Casey L, Stone Kimberley C, Ochsner Urs A, Guiles Joseph, Tarasow Ted, Janjic Nebojsa
Replidyne, Inc., Louisville, CO 80027, USA.
Antimicrob Agents Chemother. 2005 Oct;49(10):4247-52. doi: 10.1128/AAC.49.10.4247-4252.2005.
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 < or =0.5 microg/ml. REP8839 was also active against Staphylococcus epidermidis, including multiply resistant strains (MIC, < or =0.25 microg/ml). All S. pyogenes isolates were susceptible to REP8839 at concentrations of < or =0.25 microg/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 vancomycin-resistant and community-acquired methicillin-resistant isolates.
REP8839是一种新型甲硫氨酰 - tRNA合成酶(MetS)抑制剂,对金黄色葡萄球菌、化脓性链球菌及其他临床上重要的革兰氏阳性菌临床分离株具有强大的抗菌活性,而对革兰氏阴性菌活性较弱。所有金黄色葡萄球菌分离株,包括对甲氧西林、莫匹罗星、万古霉素和利奈唑胺耐药的菌株,在浓度≤0.5微克/毫升时对REP8839敏感。REP8839对表皮葡萄球菌也有活性,包括多重耐药菌株(最低抑菌浓度,≤0.25微克/毫升)。所有化脓性链球菌分离株在浓度≤0.25微克/毫升时对REP8839敏感,这表明在肺炎链球菌中先前鉴定出的第二种酶MetS2在该菌中不存在。REP8839与人血清蛋白高度结合,活性受接种量影响不大,但受pH影响,在中性培养基中而非弱酸性培养基中表现出最佳抗菌活性。与莫匹罗星一样,REP8839对关键病原体表现出抑菌活性。金黄色葡萄球菌中莫匹罗星耐药性的出现凸显了需要一种新型局部用抗生素,其能够抑制高水平莫匹罗星耐药菌株及其他新出现的表型,如万古霉素耐药和社区获得性甲氧西林耐药分离株。