Bartizal K, Gill C J, Abruzzo G K, Flattery A M, Kong L, Scott P M, Smith J G, Leighton C E, Bouffard A, Dropinski J F, Balkovec J
Antibiotic Discovery and Development, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
Antimicrob Agents Chemother. 1997 Nov;41(11):2326-32. doi: 10.1128/AAC.41.11.2326.
The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipopeptide that has been demonstrated in preclinical studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel compound. Susceptibility testing with MK-0991 against approximately 200 clinical isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to determine MICs and minimum fungicidal concentrations MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clinical isolates was 0.5 microg/ml. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compound exhibited fungicidal activity (i.e., a 99% reduction in viability) within 3 to 7 h at concentrations ranging from 0.06 to 1 microg/ml (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility of C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compound. These favorable results of preclinical studies support further studies with MK-0991 with humans.
棘白菌素MK-0991（原称L-743,872）是一种水溶性脂肽，临床前研究已证明其对念珠菌属、烟曲霉和卡氏肺孢子虫具有强大活性。对MK-0991进行了广泛的体外生物学评估，以更好地确定这种新型化合物的潜在活性。用MK-0991对约200株念珠菌、新型隐球菌临床分离株和曲霉分离株进行药敏试验，以确定最低抑菌浓度（MIC）和最低杀菌浓度（MFC）。40株白色念珠菌临床分离株中90%被抑制时的MFC为0.5μg/ml。对念珠菌和新型隐球菌耐药菌株进行的药敏试验表明，这些分离株的MK-0991 MFC与敏感分离株的MFC相当。MK-0991对白色念珠菌和热带念珠菌分离株的生长动力学研究表明，该化合物在浓度为0.06至1μg/ml（MIC的0.25至4倍）时，在3至7小时内表现出杀菌活性（即活力降低99%）。MK-0991与两性霉素B的联合用药研究发现，该联合用药在体外对白色念珠菌、新型隐球菌或烟曲霉无拮抗作用。用0%至50%的人或小鼠混合血清进行的研究表明，人或小鼠血清的存在对真菌对MK-0991的敏感性没有显著影响。耐药诱导研究结果表明，白色念珠菌反复暴露于MK-0991（40代）后敏感性未改变。用洗涤过和未洗涤过的人或小鼠红细胞进行的MK-0991红细胞溶血研究表明，该化合物的溶血潜力极小。临床前研究的这些良好结果支持对MK-0991进行进一步的人体研究。
