新型抗真菌抗生素尼可霉素Z高产菌株的育种  

Breeding of high-yielding mutant strain producing new antifungal drug nikkomycin Z

作　　者：陈姣 张勇军 陈华 

机构地区：[1]浙江省抗真菌药物重点实验室浙江海正药业股份有限公司,台州318000

出　　处：《中国抗生素杂志》2015年第9期659-662,共4页Chinese Journal of Antibiotics

基　　金：十二五"重大新药创制"科技重大专项(2012ZX09201101-004);(2012ZX09103101-075);浙江省科技计划项目(2009C33019);台州市-浙江大学科技合作专项(08ZJU007);浙江省抗真菌药物重点实验室建设项目(2007E10005);浙江省抗真菌药物重点实验室开放课题

摘　　要：目的以唐德链霉菌Streptomyces tendae ATCC 31160为原始菌株,通过选育获得高产突变株,并研究高产菌株的工业化发酵工艺。方法根据尼可霉素Z的生物合成途径,通过离子束注入方法,选育对关键中间产物2-吡啶-甲醛(PA)和3-甲基天冬氨酸的结构类似物S-(2-氨基乙基)-L-半胱氨酸(AEC)具有耐受性的突变菌株,使突变菌株的代谢能够朝着产物NIK合成的方向。结果最终筛选到一支高产突变菌株,其抗生素产量达到3000mg/L,较出发菌株提高150倍以上。在此基础上,建立了小试发酵工艺路线。结论高产突变株的筛选和发酵工艺的确定为该项目产业化奠定了基础。Objective The pyridine nucleotide antibiotic nikkomycin Z （NIK） is a chitin synthase inhibitor which acts as a competitive inhibitor, presumably due to its structural similarity to the UDP-N-acetylglucosamine （UDP-GIcNAc）. Lack of chitin in the cell wall eventually leads to osmotic lysis. The aim of this study was to select NIK high-yielding mutant from an original strain, Streptomyces tendae ATCC 31160, by the method of mutant screening. Also, the fermentation process of NIK was studied. Methods According to the biosynthetic pathway of NIK, a rational selection procedure with ion beam implantation was performed to obtain high producing strain. A mutant strain with resistance to pyridine-2-carboxaldehyde （PA） and S-（2-aminoethyl）-L-Cysteine （AEC） was obtained. Results The productivity of the selected mutant strain reached 3000mg/L which was 150 times higher than that of the parent strain. The batch fermentation process of the mutant strain was established. Conclusion The acquisition of the high-yielding mutant strain laid a foundation to achieve the industrialized production of NIK.

关 键 词：几丁质合成酶抑制剂 抗真菌药物 尼可霉素Z 高产菌株 育种 

分 类 号：R978.5[医药卫生—药品]