Selectively improving nikkomycin Z production by blocking the imidazolone biosynthetic pathway of nikkomycin X and uracil feeding in Streptomyces ansochromogenes.
BACKGROUND
Nikkomycins are a group of peptidyl nucleoside antibiotics and act as potent inhibitors of chitin synthases in fungi and insects. Nikkomycin X and Z are the main components produced by Streptomyces ansochromogenes. Of them, nikkomycin Z is a promising antifungal agent with clinical significance. Since highly structural similarities between nikkomycin Z and X, separation of nikkomycin Z from the culture medium of S. ansochromogenes is difficult. Thus, generating a nikkomycin Z selectively producing strain is vital to scale up the nikkomycin Z yields for clinical trials.


RESULTS
A nikkomycin Z producing strain (sanPDM) was constructed by blocking the imidazolone biosynthetic pathway of nikkomycin X via genetic manipulation and yielded 300 mg/L nikkomycin Z and abolished the nikkomycin X production. To further increase the yield of nikkomycin Z, the effects of different precursors on its production were investigated. Precursors of nucleoside moiety (uracil or uridine) had a stimulatory effect on nikkomycin Z production while precursors of peptidyl moiety (L-lysine and L-glutamate) had no effect. sanPDM produced the maximum yields of nikkomycin Z (800 mg/L) in the presence of uracil at the concentration of 2 g/L and it was approximately 2.6-fold higher than that of the parent strain.


CONCLUSIONS
A high nikkomycin Z selectively producing was obtained by genetic manipulation combined with precursors feeding. The strategy presented here might be applicable in other bacteria to selectively produce targeted antibiotics.
Liao
Guojian
G
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China. guojianliao@yahoo.com.cn
Li
Jine
J
Li
Lei
L
Yang
Haihua
H
Tian
Yuqing
Y
Tan
Huarong
H
D000617:Aminoglycosides / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018533:Biomass; D002687:Chitin Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism; D014498:Uracil / Q000494:pharmacology
D000617:Aminoglycosides; D000935:Antifungal Agents; D007093:Imidazoles; C117197:imidazolone; D014498:Uracil; C049372:nikkomycin X; C011952:nikkomycin; D002687:Chitin Synthase