Production of nikkomycins Bx and Bz by mutasynthesis with genetically engineered Streptomyces tendae TU901

The previously described Streptomyces tendae nikC::aph mutant was used to muta-synthesize nikkomycins B-x and B-z. The mutant is deficient in L-lysine 2-aminotransferase, which transaminates lysine to form piperideine 2-carboxylate, the precursor of the peptidyl side chain of the biologically active nikkomycins I, J, X, and Z, and is therefore unable to produce these nikkomycins. The mutant accumulates the biologically inactive biosynthetic nucleoside precursors nikkomycins C-x and C-z. Resting cell cultures of the mutant fed with benzoic acid produced the biologically active nikkomycins B-x and B-z, which contain 2-amino-4-hydroxy-3-methyl-4-(4'-hydroxyphenyl)butanoic acid as the peptidyl side chain. The structures of nikkomycins B-x and B-z were confirmed by mass spectrometry and NMR. Nikkomycins B-x and B-z exhibit significantly higher pH stability than their analogues nikkomycins X and Z.