Zurenko G E, Yagi B H, Schaadt R D, Allison J W, Kilburn J O, Glickman S E, Hutchinson D K, Barbachyn M R, Brickner S J
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
Antimicrob Agents Chemother. 1996 Apr;40(4):839-45. doi: 10.1128/AAC.40.4.839.
Oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. U-100592 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]- phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and U-100766 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]- 2-oxo-5-oxazolidinyl]methyl]-acetamide are novel oxazolidinone analogs from a directed chemical modification program. MICs were determined for a variety of bacterial clinical isolates; the respective MICs of U-100592 and U-100766 at which 90% of isolates are inhibited were as follows: methicillin-susceptible Staphylococcus aureus, 4 and 4 micrograms/ml; methicillin-resistant S. aureus, 4 and 4 micrograms/ml; methicillin-susceptible Staphylococcus epidermidis, 2 and 2 micrograms/ml; methicillin-resistant S. epidermidis, 1 and 2 micrograms/ml; Enterococcus faecalis, 2 and 4 micrograms/ml; Enterococcus faecium, 2 and 4 micrograms/ml; Streptococcus pyogenes, 1 and 2 micrograms/ml; Streptococcus pneumoniae, 0.50 and 1 microgram/ml; Corynebacterium spp., 0.50 and 0.50 micrograms/ml; Moraxella catarrhalis, 4 and 4 micrograms/ml; Listeria monocytogenes, 8 and 2 micrograms/ml; and Bacteroides fragilis, 16 and 4 micrograms/ml. Most strains of Mycobacterium tuberculosis and the gram-positive anaerobes were inhibited in the range of 0.50 to 2 micrograms/ml. Enterococcal strains resistant to vancomycin (VanA, VanB, and VanC resistance phenotypes), pneumococcal strains resistant to penicillin, and M. tuberculosis strains resistant to common antitubercular agents (isoniazid, streptomycin, rifampin, ethionamide, and ethambutol) were not cross-resistant to the oxazolidinones. The presence of 10, 20, and 40% pooled human serum did not affect the antibacterial activities of the oxazolidinones. Time-kill studies demonstrated a bacteriostatic effect of the analogs against staphylococci and enterococci but a bactericidal effect against streptococci. The spontaneous mutation frequencies of S. aureus ATCC 29213 were <3.8 x 10(-10) and <8 x 10(-11) for U-100592 and U-100766, respectively. Serial transfer of three staphylococcal and two enterococcal strains on drug gradient plates produced no evidence of rapid resistance development. Thus, these new oxazolidinone analogs demonstrated in vitro antibacterial activities against a variety of clinically important human pathogens.
恶唑烷酮类是一类相对较新的抗菌药物，具有独特的抑制细菌蛋白质合成的机制。U - 100592（S）-N-[[3-[3-氟-4-[4-(羟基乙酰基)-1-哌嗪基]-苯基]-2-氧代-5-恶唑烷酮基]甲基]-乙酰胺和U - 100766（S）-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-恶唑烷酮基]甲基]-乙酰胺是通过定向化学修饰程序得到的新型恶唑烷酮类似物。测定了多种细菌临床分离株的最低抑菌浓度（MIC）；U - 100592和U - 100766使90%分离株受到抑制的各自MIC如下：甲氧西林敏感金黄色葡萄球菌，4和4微克/毫升；耐甲氧西林金黄色葡萄球菌，4和4微克/毫升；甲氧西林敏感表皮葡萄球菌，2和2微克/毫升；耐甲氧西林表皮葡萄球菌，1和2微克/毫升；粪肠球菌，2和4微克/毫升；屎肠球菌，2和4微克/毫升；化脓性链球菌，1和2微克/毫升；肺炎链球菌，0.50和1微克/毫升；棒状杆菌属，0.50和0.50微克/毫升；卡他莫拉菌，4和4微克/毫升；单核细胞增生李斯特菌，8和2微克/毫升；脆弱拟杆菌，16和4微克/毫升。大多数结核分枝杆菌菌株和革兰氏阳性厌氧菌在0.50至2微克/毫升范围内受到抑制。对万古霉素耐药的肠球菌菌株（VanA、VanB和VanC耐药表型）、对青霉素耐药的肺炎链球菌菌株以及对常用抗结核药物（异烟肼、链霉素、利福平、乙硫异烟胺和乙胺丁醇）耐药的结核分枝杆菌菌株对恶唑烷酮类没有交叉耐药性。加入10%、20%和40%的混合人血清不影响恶唑烷酮类的抗菌活性。时间-杀菌研究表明，这些类似物对葡萄球菌和肠球菌有抑菌作用，但对链球菌有杀菌作用。金黄色葡萄球菌ATCC 29213对U - 100592和U - 100766的自发突变频率分别<3.8×10⁻¹⁰和<8×10⁻¹¹。在药物梯度平板上对三株葡萄球菌和两株肠球菌菌株进行连续传代，未发现快速产生耐药性的证据。因此，这些新型恶唑烷酮类似物在体外对多种临床上重要的人类病原体具有抗菌活性。
