Diazaquinomycin A, a new antifolate antibiotic, inhibits thymidylate synthase

The inhibitory effect of diazaquinomycin A (DQM) on the growth of Enterococcus faecium was completely reversed by thymidine. Relatively large amounts of folate, dihydrofolate or leucovorin also reversed the activity of DQM. DQM showed cytotoxicity against Vero and Raji cells and the cytotoxicity was partially reversed by leucovorin or thymidine. With enzyme experiments, it was found that DQM inhibits TMP synthases from E. faecium and Ehrlich ascites carcinoma competitively with 5,10-methylenetetrahydrofolate, one of the substrates for the enzyme reaction.