Thiolactomycin, a new antibiotic. II. Structure elucidation.

Sasaki, Hiroshi; Oishi, Hideo; Hayashi, Toshiaki; Matsuura, I.; Ando, Kiyoshi; Sawada, Mikio

doi:10.7164/antibiotics.35.396

Cited by 72 publications

(43 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…,B-Ketoacyl-ACP synthase III selectively catalyzes the formation of acetoacetyl-ACP in vitro (17). The role of this third condensing enzyme remains to be established, but its position at the beginning of the biosynthetic pathway suggests that it plays a role in governing the total rate of fatty acid production.Thiolactomycin [(4S)(2E,5E)-2,4,6-trimethyl-3-hydroxy-2,5,7-octatriene-4-thiolide] (TLM) is a unique antibiotic structure that inhibits type II (bacterial and plant) but not type I (yeast and mammalian) fatty acid synthases (14,15,25,26,31). The antibiotic is not toxic to mice and affords significant protection against urinary tract and intraperitoneal bacterial infections (23).…”

mentioning

confidence: 99%

“…Thiolactomycin [(4S)(2E,5E)-2,4,6-trimethyl-3-hydroxy-2,5,7-octatriene-4-thiolide] (TLM) is a unique antibiotic structure that inhibits type II (bacterial and plant) but not type I (yeast and mammalian) fatty acid synthases (14,15,25,26,31). The antibiotic is not toxic to mice and affords significant protection against urinary tract and intraperitoneal bacterial infections (23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Overproduction of beta-ketoacyl-acyl carrier protein synthase I imparts thiolactomycin resistance to Escherichia coli K-12

1992

View full text Add to dashboard Cite

Thiolactomycin [(4S)(2E,5E)-2,4,6-trimethyl-3-hydroxy-2,5,7-octatriene-4-thiolide] (TLM) is a unique antibiotic structure that inhibits dissociated type II fatty acid synthase systems but not the multifunctional type I fatty acid synthases found in mammals. We screened an Escherichia coli genomic library for recombinant plasmids that impart TLM resistance to a TLM-sensitive strain of E. coli K-12. Nine independent plasmids were isolated, and all possessed a functional I8-ketoacyl-acyl carrier protein synthase I gene (fabB) based on their restriction enzyme maps and complementation of the temperature-sensitive growth of a fabBIS(Ts) mutant. A plasmid (pJTB3) was constructed that contained only the fabB open reading frame. This plasmid conferred TLM resistance, complemented thefabB(Ts) mutation, and directed the overproduction of synthase I activity. TLM selectively inhibited unsaturated fatty acid synthesis in vivo; however, synthase I was not the only TLM target, since supplementation with oleate to circumvent the cellular requirement for an active synthase I did not confer TLM resistance. Overproduction of the FabB protein resulted in TLM-resistant fatty acid biosynthesis in vivo and in vitro. These data show that ,I-ketoacyl-acyl carrier protein synthase I is a major target for TLM and that increased expression of this condensing enzyme is one mechanism for acquiring TLM resistance. However, extracts from a TLM-resistant mutant (strain CDM5) contained normal levels of TLM-sensitive synthase I activity, illustrating that there are other mechanisms of TLM resistance.The 3-ketoacyl-acyl carrier protein (ACP) synthases are key regulators of dissociated (type II) fatty acid synthase systems typified by the Escherichia coli system (for reviews, see references 5 and 28). ,-Ketoacyl-ACP synthase I is required for a critical step in the elongation of unsaturated acyl-ACP, and mutants (fabB) lacking synthase I activity are unable to synthesize either palmitoleic or cis-vaccenic acid and require supplementation with unsaturated fatty acids for growth (6, 30). 13-Ketoacyl-ACP synthase II is responsible for the temperature-dependent regulation of fatty acid composition (for a review, see reference 7). Mutants (fabF) lacking synthase II activity are deficient in cis-vaccenic acid but grow normally (11,12). ,B-Ketoacyl-ACP synthase III selectively catalyzes the formation of acetoacetyl-ACP in vitro (17). The role of this third condensing enzyme remains to be established, but its position at the beginning of the biosynthetic pathway suggests that it plays a role in governing the total rate of fatty acid production.Thiolactomycin [(4S)(2E,5E)-2,4,6-trimethyl-3-hydroxy-2,5,7-octatriene-4-thiolide] (TLM) is a unique antibiotic structure that inhibits type II (bacterial and plant) but not type I (yeast and mammalian) fatty acid synthases (14,15,25,26,31). The antibiotic is not toxic to mice and affords significant protection against urinary tract and intraperitoneal bacterial infections (23). Understanding the mechanism of TLM ac...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Overproduction of beta-ketoacyl-acyl carrier protein synthase I imparts thiolactomycin resistance to Escherichia coli K-12

1992

View full text Add to dashboard Cite

show abstract

“…15 Several compounds, thiolactomycin, plantensimycin and platencin, have been isolated from actinomycete strains as inhibitors of type II fatty acid synthase. [16][17][18][19] Interestingly, calpinactam and lariatin, 9 on which we reported previously, have the same characteristics as the above-mentioned clinical agents, showing selective growth inhibition against mycobacteria (Table 1). Calpinactam has almost no cytotoxic activity against Jurkat cells up to at least 25 mg ml À1 .…”

Section: Discussionmentioning

confidence: 55%

Calpinactam, a new anti-mycobacterial agent, produced by Mortierella alpina FKI-4905

et al. 2010

View full text Add to dashboard Cite

Calpinactam, a new anti-mycobacterial agent, was isolated from the culture broth of a fungal strain Mortierella alpina FKI-4905 by solvent extraction, octadecyl silane column chromatography and preparative HPLC. Calpinactam was active only against Mycobacteria among various microorganisms, including Gram-positive and Gram-negative bacteria, fungi and yeasts. Calpinactam inhibited the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis with MIC values of 0.78 and 12.5 lg ml À1 , respectively. The Journal of Antibiotics (2010) 63, 183-186; doi:10.1038/ja.2010.14; published online 26 February 2010Keywords: anti-mycobacterial peptide; calpinactam; fungal metabolite; mycobactin; tuberculosis INTRODUCTIONOur research group has focused on the discovery of anti-infectives from microbial metabolites. 1-5 Tuberculosis (TB) is still the greatest single infectious cause of mortality in the world, together with human immunodeficiency virus and malaria. 6 Moreover, the spread of human immunodeficiency virus has resulted in an increase in the number of TB patients. 7 However, no new anti-TB agents have been developed for over 30 years, and only five anti-TB drugs can be used clinically at present. It is therefore increasingly urgent and necessary to discover anti-TB drugs with a new mechanism of action. As isoniazid and ethambutol, first-line anti-TB drugs, show selective inhibition against Mycobacteria, we have screened for microbial metabolites having selective inhibition against Mycobacterium smegmatis among 14 test microorganisms, including Gram-positive and Gram-negative bacteria, fungi and yeasts. By this screening system, we discovered and reported lariaitins, new lasso polypeptides, from actinomycete Rhodococcus metabolites. [8][9][10] During the continuous screening program, we isolated calpinactam (Figure 1), a new hexapeptide with a caprolactam ring at the C-terminal, from the culture broth of the fungal strain Mortierela alpina FKI-4905 (Figure 2). The structure elucidation of calpinactam is described in detail elsewhere. 11 In this report, the taxonomy of the producing strain, fermentation, isolation and biological properties of calpinactam are described.

show abstract

“…The validity of the structure as a 5-membered thiolactone was also supported by the spectroscopic characterization of two monomethyl ethers, 3 These spectral data demonstrated that 4 is an tautomeric isomer of 3. The synthesis of 1 and its related compounds are now in progress.…”

mentioning

confidence: 74%