Recent Progress of Taxonomic Studies on Pathogenic Nocardia and Usefulness of the Bacteria for the Studies on Secondary Metabolites and Antibiotic Resistant Mechanisms

Abstract

The present taxonomic situation of pathogenic actinomycetes including Nocardia was clarified, and the impact of genomic sequence information of Nocardia farcinica IFM 10152 on taxonomic work is introduced. The number of cases of nocardiosis is on the rise along with the increasing number of immunocompromised patients in Japan. From 1999 to 2007, 718 strains of pathogenic actinomycetes were received for identification by Medical Mycology Research Center (MMRC), Chiba University. About 75% of these were classified into Nocardia, major species being N. farcinica, N. nova, and N. brasiliensis. Among the strains classified as Nocardia species, there were some unclassifiable strains and taxonomic studies on these led to the proposal of more than 18 new species, resulting in more than 1/4 of all Nocardia species having been proposed by our group. Recently a new Nocardia species, Nocardia mikamii was proposed by American researchers. A new phylogenetic analysis method using gryB and secA1 genes was proposed for the Nocardia and Gordonia strains.Our whole genome analysis of N. farcinica suggests that the bacterium has unique and characteristic gene profiles, and also suggests that N. farcinica is similar to Mycobacterium tuberculosis. N. farcinica also has siderophore (nocobactin) and mce genes which are similar to mycobactin (siderophore) of M. tuberculosis as virulence factors. Nocardia strains were found to be producers of new secondary metabolites including antifungal, antitumor and immunosuppressive activities.We reported novel antibiotic resistance mechanisms such as ribosylation, glucosylation, phosphorylation and degradation of rifampicin, phosphorylation of aminoglycosides, and glucosylation of macrolide antibiotics. Among rifampicin inactivation mechanisms, ribosylation was found to be through the Arr enzyme that catalyzes ADP-ribosylation of rifampicin in a fast-growing Mycobacterium smegmatis. This unique mechanism has also been reported as an antibiotic resistant mechanism in pathogenic Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii.Our cooperative work on the elucidation of high-level resistance to the aminoglycoside antibiotic amikacin in N. farcinica with a research group from CDC, USA, revealed the presence of homozygous mutations in the 16R rRNA genes which are responsible for high-level aminoglycoside antibiotic resistance.