Nocathiacins, New Thiazolyl Peptide Antibiotics from Nocardia sp. I. Taxonomy, Fermentation and Biological Activities.

Li, Wenying; Leet, John E.; Ax, Helen A.; Gustavson, Donald R.; Brown, D. M.; Turner, Laura; Brown, Kimberly; Clark, Junius M.; Yang, Hao; Fung‐Tomc, Joan; Lam, Kentson

doi:10.7164/antibiotics.56.226

Cited by 109 publications

(72 citation statements)

References 20 publications

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“…Although the function of these genes is not clear except for nbtD-nbtF, some of them are possibly involved in the production of novel peptides with biological activity, such as thiazolyl peptide antibiotics previously isolated from Nocardia sp. (31).…”

Section: Resultsmentioning

confidence: 99%

The complete genomic sequence of Nocardia farcinica IFM 10152

Ishikawa

Yamashita

Mikami

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

268

202

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We determined the genomic sequence of Nocardia farcinica IFM 10152, a clinical isolate, and revealed the molecular basis of its versatility. The genome consists of a single circular chromosome of 6,021,225 bp with an average G؉C content of 70.8% and two plasmids of 184,027 (pNF1) and 87,093 (pNF2) bp with average G؉C contents of 67.2% and 68.4%, respectively. The chromosome encoded 5,674 putative protein-coding sequences, including many candidate genes for virulence and multidrug resistance as well as secondary metabolism. Analyses of paralogous protein families suggest that gene duplications have resulted in a bacterium that can survive not only in soil environments but also in animal tissues, resulting in disease.N ocardia are filamentous-growing Gram-positive soil saprophytes that belong to the family Actinomycetales, which also includes clinically and industrially important genera such as Mycobacterium, Streptomyces, Corynebacterium, and Rhodococcus. Many species of Nocardia cause the disease nocardiosis in humans and animals on lung, central nervous system, brain, and cutaneous tissues (1), and a species Nocardia asteroides is suspected to be an etiological agent of Parkinson's disease (2). Nocardiosis is on the rise, with an estimated 109-136 new cases occurring annually in Japan (3) and 500-1,000 in the U.S. (www.cdc.gov͞ncidod͞dbmd͞diseaseinfo͞nocardiosis t.htm). However, there are only a few studies on the mechanisms of nocardial virulence. Nocardia species are resistant to many front-line antibiotics. Because treatment for nocardiosis relies heavily on chemotherapy, their intrinsic multiple drug resistance is a serious problem.Another feature of the nocardia is that many strains, even clinical isolates, also have the capability to produce bioactive molecules such as antibiotics (4, 5) and enzymes that are industrially important (6). A monobactam antibiotic, nocardicin, was isolated from Nocardia sp. (7), and a terpenoid brasilicardin with immunosuppressive activity was isolated from a clinical isolate (4).Nocardia farcinica IFM 10152 was isolated from the bronchus of a 68-year-old male Japanese patient. Despite the complicated taxonomy of the nocardia, the species N. farcinica was found to be nearly homogeneous (8). Subsequently, to elucidate the molecular basis of the versatility of the nocardia, we analyzed the genomic sequence of N. farcinica IFM 10152. MethodsGenome Sequencing and Assembly. The nucleotide sequence of the N. farcinica IFM 10152 genome was determined by a wholegenome shotgun strategy. We constructed small-insert (2 kb) and large-insert (10 kb) genomic libraries and generated 127,077 sequences (giving 9-fold coverage) from both ends of the genomic clones. Sequence assembly was carried out by using the PHRED͞PHRAP͞CONSED package (9). Remaining gaps were closed by transcriptional sequencing (Nippon Gene, Toyama, Japan) or by primer walking. There were no ambiguous nucleotides in the genomic sequence that we could determine. Consistency of the final assembly was confirmed in terms of res...

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Section: Resultsmentioning

confidence: 99%

The complete genomic sequence of Nocardia farcinica IFM 10152

Ishikawa

Yamashita

Mikami

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

268

202

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“…Significant advances in biology and chemistry have taken place since then. Upon closer examination of this chemical class, compounds such as glycothiohexide a [10,11], S54832A-I [7], MJ347-81F4A and B [12] and nocathiacins [13,14] appeared more attractive than the rest because they contained aminoglycosidic residue, which inherently provided potential for improvement of aqueous solubility. This was illustrated by chemical modifications of nocathiacin I [13ϳ23].…”

Section: Isolation and Structure Elucidation Of Thiazomycinmentioning

confidence: 99%

“…These data indicated that the structural differences resided in the amino sugar residue. The complete set of 1 H-, 13 C-, COSY, HMQC and HMBC data was recorded in DMSO and in a mixed solvent consisting of CDCl 3 /CD 3 OD 5 : 1. The mixed solvent system produced much better resolution and sharpness of the 1 H-NMR signals and yielded a better data set which was used in the structure elucidation (Table 1).…”

Section: Structure Elucidationmentioning

confidence: 99%

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Isolation and Structure Elucidation of Thiazomycin

et al. 2007

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Thiazolyl peptides are a class of rigid macrocyclic compounds richly populated with thiazole rings. They are highly potent antibiotics but none have been advanced to clinic due to poor aqueous solubility. Recent progress in this field prompted a reinvestigation leading to the isolation of a new thiazolyl peptide, thiazomycin, a congener of nocathiacins. Thiazomycin possesses an oxazolidine ring as part of the amino-sugar moiety in contrast to the dimethyl amino group present in nocathiacin I. The presence of the oxazolidine ring provides additional opportunities for chemical modifications that are not possible with other nocathiacins. Thiazomycin is extremely potent against Gram-positive bacteria both in vitro and in vivo. The titer of thiazomycin in the fermentation broth was very low compared to the nocathiacins I and III. The lower titer together with its sandwiched order of elution presented significant challenges in large scale purification of thiazomycin. This problem was resolved by the development of an innovative preferential protonation based one-and/or two-step chromatographic method, which was used for pilot plant scale purifications of thiazomycin. The isolation and structure elucidation of thiazomycin is herein described.

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“…1A) produced by Nocardia sp. ATCC202099 (18,19), which represents the most pharmaceutically promising members of the thiopeptide antibiotics numbering Ͼ80 entities reported to date. This indicates that NosL homologs might be involved in the biosynthetic pathways of all the e-series thiopeptides for the MIA moiety formation.…”

mentioning

confidence: 99%

Characterization of NocL Involved in Thiopeptide Nocathiacin I Biosynthesis

Zhang

Chen

Lin

et al. 2011

Journal of Biological Chemistry

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The radical S-adenosylmethionine (AdoMet) enzyme superfamily is remarkable at catalyzing chemically diverse and complex reactions. We have previously shown that NosL, which is involved in forming the indole side ring of the thiopeptide nosiheptide, is a radical AdoMet enzyme that processes L-Trp to afford 3-methyl-2-indolic acid (MIA) via an unusual fragmentation-recombination mechanism. We now report the expansion of the MIA synthase family by characterization of NocL, which is involved in nocathiacin I biosynthesis.

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Nocathiacins, New Thiazolyl Peptide Antibiotics from Nocardia sp. I. Taxonomy, Fermentation and Biological Activities.

Cited by 109 publications

References 20 publications

The complete genomic sequence of Nocardia farcinica IFM 10152

The complete genomic sequence of Nocardia farcinica IFM 10152

Isolation and Structure Elucidation of Thiazomycin

Characterization of NocL Involved in Thiopeptide Nocathiacin I Biosynthesis

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