Identification of a new oligomycin derivative as a specific inhibitor of the alternative peptidoglycan biosynthetic pathway.

Peptidoglycan is an important macromolecule in bacterial cell walls to maintain cell integrity, and its biosynthetic pathway has been well studied. Recently, we demonstrated that some bacteria such as Xanthomonas oryzae, a pathogen causing bacterial blight of rice, used an alternative pathway for peptidoglycan biosynthesis. In this pathway, MurD2, a MurD homolog, catalyzed the attachment of L-Glu to UDP-MurNAc-L-Ala and MurL, which did not show homology to any known protein, catalyzed epimerization of the terminal L-Glu of the MurD2 product to generate UDP-MurNAc-L-Ala-D-Glu. Because the alternative pathway also operates in some other plant pathogens and opportunistic pathogens, specific inhibitors of the alternative pathway could function as pesticides and antibiotics for these pathogens. In this study, we searched for specific inhibitors of the alternative pathway from metabolites produced by actinomycetes and identified a new oligomycin-class polyketide, which was revealed to inhibit the MurD2 reaction, in culture broth of Micromonospora sp. K18-0097.

Identification of pulvomycin as an inhibitor of the futalosine pathway.

Menaquinone is an essential cofactor in the electron-transfer pathway for bacteria. Menaquinone is biosynthesized from chorismate using either the well-known canonical pathway established by pioneering studies in model microorganisms or the futalosine pathway, which we discovered in Streptomyces. Because Helicobacter pylori, which causes stomach cancer, uses the futalosine pathway and most beneficial intestinal bacteria including lactobacilli use the canonical pathway, the futalosine pathway will be a great target to develop antibiotics specific for H. pylori. Here, we searched for such compounds from metabolites produced by actinomycetes and identified pulvomycin from culture broth of Streptomyces sp. K18-0194 as a specific inhibitor of the futalosine pathway.