Metabolic engineering of a methyltransferase for production of drug precursors demecycline and demeclocycline in Streptomyces aureofaciens

Demecycline(DMTC)and demeclocycline(DMCTC)are C6-demethylated derivatives of tetracycline(TC)and chlortetracycline(CTC),respectively.They are precursors of minocycline and tigecycline,which showed remarkable bioactivity against TC-resistant bacteria and have been used clinically for decades.In order to biosynthesize drug precursors DMTC and DMCTC,the function of a possible C-methyltransferase encoding gene ctcK was studied systematically in the CTC high-yielding industrial strain Streptomyces aureofaciens F3.TheΔctcK mutant accumulated two new products,which were turned out to be DMTC and DMCTC.Meanwhile,timecourse analysis of the fermentation products detected the epimers of DMTC and DMCTC transformed spontaneously.Finally,an engineering strain with higher productivity of DMCTC was constructed by deleting ctcK and overexpressing ctcP of three extra copies simultaneously.Construction of these two engineering strains not only served as a successful example of synthesizing required products through metabolic engineering,but also provided original strains for following elaborate engineering to synthesize more effective tetracycline derivatives.

From Russia with Polyuria

Introduction: Polyuria is a sign for many disease processes, including diabetes mellitus and diabetes insipidus. Urine osmolarity helps distinguish osmotic diuresis caused by diabetes mellitus from water dieresis induced by diabetes insipidus. Case Presentation: We report a case of a 48-year-old woman who presented with polyuria, polydipsia, nocturia, and weight loss after a return from a visit to Russia, during which she received a five-day course of antibiotic Demeclocycline, a tetracycline derivative for dental treatment. She recovered from all clinical manifestations by 8 weeks. Conclusion: Manifestation of transient nephrogenic diabetes insipidus is induced by Demeclocycline.