Nocardia species are the causative agents of nocardiosis in humans and are known to produce a variety of bioactive compounds with antimicrobial, antitumor and immunosuppressive activities. Nocardia brasiliensis is often reported to produce various bioactive compounds such as indole alkaloid, terpenoid, peptide and aromatic compounds.1 Other species, including N. asteroides and N. farcinica, are not widely reported to be producers of bioactive compounds, and their products are generally siderophores.2, 3 Reports regarding the production of polyketide compounds, such as macrolides and polyethers, synthesized by modular type-I polyketide synthases (PKS-Is), are limited to a few species such as N. brasiliensis and N. terpenica,4, 5, 6, 7 although some polyketide-producing Nocardia strains are yet to be identified at the species level.8 The recent N. farcinica IFM 10152 genome sequencing project revealed the presence of only six PKS-I genes, suggesting that PKS-I genes are less abundant in N. farcinica compared with Streptomyces spp.9, 10, 11 Nfa7640 (nbtB) and nfa7650 (nbtC) are PKS-I genes in a mixed PKS/non-ribosomal peptide synthetase (NRPS) gene cluster involved in the synthesis of siderophores named nocobactins;2 however, metabolites of the other four PKS-I genes, nfa1890, nfa30250, nfa43240 and nfa55930, are still unclear, although nfa30250 is predicted to be mycocerosic acid synthase. Because none of these four genes organizes multimodular PKS-I gene clusters, their metabolites are not likely to be structurally complex and the strain will not produce typical polyketide compounds, such as macrolides and polyethers. This may be one reason why type-I polyketide compounds are not frequently produced by Nocardia. The biosynthetic potential of actinomycetes is often approximated through the analysis of genes involved in synthesis of secondary metabolites, such as PKS-Is, type-II PKSs and NRPSs.12, 13, 14, 15 However, the diversity and novelty of these genes in Nocardia species other than N. farcinica have not been studied. There is no information regarding the relationship between taxonomy and gene distribution. In our study, we focused on PKS-I genes and investigated their relationship with Nocardia taxonomy. This allowed us to assess their ability to produce various type-I polyketide compounds.

Recent genetic analyses of biosynthesis pathways for secondary metabolites have demonstrated their crucial roles in the discovery of novel natural products. Ayuso-Sacido and Genilloud13 examined the distribution of PKS-I genes in Nocardia strains using a PCR assay, and found that 69% (11/16) of the strains were positive for the presence of PKS-I genes. This was comparable to that in Streptomyces (79%, 26/33); however, sequence diversity in Nocardia has not been thoroughly examined.12 We demonstrated that all the Nocardia strains tested in this study contained PKS-I genes and the diversity varied among taxonomic species. The 13 species possessed mainly universal PKS-I genes. Although the KS sequences were grouped into two clades, as shown by the phylogenetic analysis, the relationship between the two groups is still unclear from this study. We are sequencing the full-length PKS gene cluster(s) in some strains to clarify this relationship. In contrast, the universal PKS-I genes were not detected in the other nine species shown in Figure 1. The sequences of KS domains in these nine species were different (<70% identity) from the universal sequences and each other. Therefore, these species will be useful in screening sources for discovering novel types of polyketide compounds. As mentioned previously, N. brasiliensis and N. terpenica are known to be a useful source of various bioactive compounds. In this study, we revealed that some species, including N. brasiliensis and N. terpenica, had unique and diverse PKS-I genes. In contrast, reports of type-I polyketide products from other species are limited.2, 8, 9 This might be due to the poor PKS-I diversity in some species, in which universal PKS-I genes are dominant. It would be valuable to extensively analyze PKS-I genes in Nocardia strains and determine any relationship with their taxonomy.

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