阿扎霉素F衍生物及联合维生素K_3抗耐甲氧西林金黄色葡萄球菌研究

The anti-methicillin-resistant Staphylococcus aureus activities of azalomycin F derivatives and those of them combined with vitamin K_3

目的发现高效抗耐甲氧西林金黄色葡萄球菌（MRSA）的N#L霉素F衍生物。方法以阿扎霉素F为原料，通过氢化钠水解脱去丙二酸单酰基制得阿扎霉素F衍生物；然后以MRSAATCC33592和临床菌株MRSA01～03为指示菌，采用微量肉汤稀释法和棋盘格法设计试验，测定阿扎霉素F衍生物的最低抑菌浓度及联合维生素K3的抗MRsA作用。结果合成制得的去丙二酸单酰基阿扎霉素F5a、F4a和F3a对MRSA测试菌株的最低抑菌浓度分别为0．25～0．50、0．25和0．25～0．50μg／mL，最低杀菌浓度分别为1、1和2μg／mL；与维生素K3联合抗MRSA的部分抑菌浓度指数（FICIs）均为0．38～0．50。结论制得的阿扎霉素F衍生物具有显著抗MRSA活性，为阿扎霉素F的8～16倍，且强于阳性对照药利奈唑胺，同时与维生素K3具有协同抗MRSA作用，显示其作为新型抗MRSA大环内酯的良好研发前景。

Objective To discover anti-methicillin-resistant Staphylococcus aureus （anti-MRSA） azalomycin F derivatives. Methods Through one-step hydrolysis reaction using sodium hydride in methanol, azalomycin F derivatives were synthesized. Against a reference strain MRSA ATCC 33592 and three clinical isolates MRSA 01-03, the minimum inhibitory concentrations （MICs） and minimum bactericidal concentrations （MBCs） of three azalomycin F derivatives were determined by broth microdilution method, and linezolid was used as positive control. Their anti- MRSA effects combined with vitamin K3 were determined on 96-well plate using checkerboard design. Results Three azalomycin F derivatives as demalonyl azalomycins F5a, F4a and Faa were obtained. Their MICs against all MRSA strains tested were successively 0.25-0.50, 0.25 and 0.25-0.50μg/mL, and all their MBCs were respectively 1, 1 and 2μg/mL, and all the fractional inhibitory concentration indices （FICIs） of them combined with vitamin K3 were 0.38-0.50. Conclusion Demalonyl azalomycin F have remarkable anti-MRSA activities which were 8 to 16 times to those of azalomycin F, and have synergistic anti-MRSA effects combined with vitamin K3. As new anti-MRSA macrocyclides, demalonyl azalomycin F are further worthy researching and developing.