Abstract
Nocardithiocin is a thiopeptide compound isolated from the opportunistic pathogen Nocardia pseudobrasiliensis. It shows a strong activity against acid-fast bacteria and is also active against rifampicin-resistant Mycobacterium tuberculosis. Here, we report the identification of the nocardithiocin gene cluster in N. pseudobrasiliensis IFM 0761 based on conserved thiopeptide biosynthesis gene sequence and the whole genome sequence. The predicted gene cluster was confirmed by gene disruption and complementation. As expected, strains containing the disrupted gene did not produce nocardithiocin while gene complementation restored nocardithiocin production in these strains. The predicted cluster was further analyzed using RNA-seq which showed that the nocardithiocin gene cluster contains 12 genes within a 15.2-kb region. This finding will promote the improvement of nocardithiocin productivity and its derivatives production.
Highlights
Actinomycetes are Gram-positive soil bacteria that produce various secondary metabolites
Prior to attempting to identify the nocardithiocin biosynthetic gene cluster, we confirmed the nocardithiocin production of 14 N. pseudobrasiliensis strains stocked at the Medical Mycology Research Center, Chiba University, Japan (Table 1)
To locate the nocardithiocin biosynthetic gene cluster in the N. pseudobrasiliensis genome, we first tried to identify the cyclodehydratase genes, which are relatively conserved among bacterial strains and required for thiopeptide biosynthesis [10]
Summary
Actinomycetes are Gram-positive soil bacteria that produce various secondary metabolites. Secondary metabolite production in Nocardia species is less well studied, a recent genome-based analysis revealed that the number of secondary metabolite gene clusters in Nocardia species is comparable with that of Streptomyces species [3]. Mukai et al identified a thiopeptide compound, nocardithiocin, from Nocardia pseudobrasiliensis [4] (Fig 1).Thiopeptides (thiazolyl peptides) are highly modified sulfur-rich peptides synthesized by the ribosome These compounds all contain a central nitrogen-containing six-membered ring, which serves as the scaffold for at least one macrocycle and a tail. These compounds possess a wide range of bioactivities, including antimicrobial, anticancer, and antiplasmodial effects. In addition to these clinically promising activities, this family of PLOS ONE | DOI:10.1371/journal.pone.0143264 November 20, 2015
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