Selectively improving nikkomycin Z production by blocking the imidazolone biosynthetic pathway of nikkomycin X and uracil feeding in Streptomyces ansochromogenes.

Guojian Liao,Jine Li,Haihua Yang,Yuqing Tian,Lei Li,Huarong Tan

doi:10.1186/1475-2859-8-61

Abstract

BackgroundNikkomycins 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.ResultsA 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.ConclusionA 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.

Highlights

Nikkomycins are a group of peptidyl nucleoside antibiotics and act as potent inhibitors of chitin synthases in fungi and insects
Nikkomycins, a group of peptidyl nucleoside antibiotics produced by Streptomyces ansochromogenes [1] and Streptomyces tendae [2], are potent competitive inhibitors of chitin synthase
Construction of the nikkomycin Z selectively producing strain To obtain an ideal strain only producing nikkomycin Z, the disruption of sanP in S. ansochromogenes TH322 was performed (Fig. 3A). sanP is an homologue of nikP2 of S. tendae, which is vital for the biosynthesis of imidazolone that is an unique part of nikkomycin X [13]

Summary

Introduction

Nikkomycins are a group of peptidyl nucleoside antibiotics and act as potent inhibitors of chitin synthases in fungi and insects. Nikkomycins, a group of peptidyl nucleoside antibiotics produced by Streptomyces ansochromogenes [1] and Streptomyces tendae [2], are potent competitive inhibitors of chitin synthase. These antibiotics are structurally similar to UDP-N-acetylglucosamine which is the natural substrate of chitin synthase. They can inhibit the growth of insects, acarids, yeasts, and filamentous fungi [3]. Nikkomycin Z has synergetic effect with azoles and echinocandins against Candida albicas and Aspergillus fumigatus [6,7,8]

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