Genetically engineered Streptomyces viridosporus ATCC 14672 strains for the discovery of novel moenomycins

Streptomyces viridosporus (formerly ghanaensis) ATCC14672 is the best-studied producer of moenomycins, a family of phosphoglycolipid natural products directly inhibiting peptidoglycan glycosyltransferases. The uniqueness of moenomycins, in terms of structure and mode of action, and their extreme potency against several Gram-positive pathogens (including vancomycin- and methicillin-resistant cocci), are their advantages as a drug candidate. However, they are not orally bioavailable; in the bloodstream, moenomycins are characterized by an exceedingly long half-life. These shortcomings are thought to be caused by the long C25 lipid chain (moenocinol) of moenomycins. Here we report the generation and initial studies of two ATCC 14672 mutants to access a greater diversity of moenomycins around its lipid chain. The dO5 mutant cannot produce any moenomycins due to the deletion of the moeO5 gene for the first step in moenomycin assembly. The M12 mutant of ATCC 14672 (knockout of the prenyltransferase gene moeN5) accumulates moenomycins with a C15 lipid chain instead of moenocinol. We demonstrate and discuss the potential applications of the dO5 and M12 mutants for the discovery of novel moenomycins and their genetic determinants.