Structures and absolute configurations of carpetimycins A and B.

Nakayama, Masahito; Kimura, Shigeru; Tanabe, Seiichi; Mizoguchi, Toshimi; Watanabe, Isamu; Mori, Toshihito; Miyahara, Kazumoto; Kawasaki, Terukazu

doi:10.7164/antibiotics.34.818

Cited by 32 publications

(10 citation statements)

References 8 publications

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“…However, a query of the ATCC and NRRL catalogs did not yield S. argenteolus ATCC 31589, but a different strain of S. argenteolus , ATCC 11009. S. argenteolus ATCC 11009 was also reported to produce carbapenems and carbapenams such as an olivanic acid complex and 17927 D [10c, 12] , but identifications have not been published [12b] . As the first step in our investigation, we conducted small-scale fermentation of S. argenteolus ATCC 11009 in OMYM and ISP4 + media, which showed antibiotic activity against the β-lactam super-sensitive E. coli ESS and inhibition of the β-lactamase in Klebsiella pneumoniae subsp.…”

Section: Resultsmentioning

confidence: 99%

“…Co-injection with a synthetic asparenomycin A standard showed a different retention time and UV spectrum, strongly indicating that the asparenomycins originally reported from S. argenteolus ATCC 31589 are not produced in S. argenteolus ATCC 11009 [10b, 11b] . Reaction with hydroxylamine resulted in the loss of that peak, consistent with the presence of a β-lactam in the active product.…”

Section: Resultsmentioning

confidence: 99%

“…Sequence analysis suggests and biochemical studies confirmed that ThnE and ThnM in the thienamycin biosynthetic pathway mirror the chemistry of CarB and CarA in the simple carbapenem pathway [6a, 6c] . Alignment of CarA ( P. carotovorum ), β-LS ( S. clavuli-gerus ), β-LS3 ( S. antibioticus ), CpmA ( P. luminescens ), ThnM ( S. cattleya ), and several Asn-B (asparagine synthetase) revealed two motifs (M1 and M2) highly conserved in the β-lactam forming enzymes but either absent or present at distinctly lower homology in asparagine synthetases (Asn-B).…”

Section: Resultsmentioning

confidence: 99%

“…Enzymatic analysis has demonstrated that the differences in the level of oxidation of the C-6 and C-2 side chains and C-6 stereochemistry give rise to many structural combinations [10] . It remains unknown how these differences are genetically encoded to produce potent antibiotics, distinct from thienamycin.…”

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of the Carbapenem MM 4550 and its Gene Cluster in Streptomyces argenteolus ATCC 11009

Lloyd

Moshos

et al. 2014

ChemBioChem

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Nearly 50 naturally-occurring carbapenem β-lactam antibiotics, most produced by Streptomyces, have been identified. The structural diversity of these compounds is limited to variance of the C-2 and C-6 side chains as well as the stereochemistry at C-5/C-6. These structural motifs are of interest both for their antibiotic effects and their biosynthesis. While the thienamycin gene cluster is the only active gene cluster publically available in this group, more comparative information is needed to understand the genetic basis of these structural differences. We report here the identification of MM 4550, a member of the olivanic acids, as the major carbapenem produced by S. argenteolus ATCC 11009. Its gene cluster was also identified by degenerate PCR and targeted gene inactivation. Sequence analysis revealed that genes encoding the biosynthesis of the bicyclic core and the C-6 and C-2 side chains are well conserved in the MM 4550 and thienamycin gene clusters. Three new genes, cmmSu, cmm17 and cmmPah were found in the new cluster and their putative functions in the sulfonation and epimerization of MM 4550 are proposed. Gene inactivation showed that, in addition to cmmI, two new genes, cmm22/23, encode a two-component response system thought to regulate the production of MM 4550. Overexpression of cmmI, cmm22 and cmm23 promoted MM 4550 production in an engineered strain. Finally, the involvement and putative roles of all genes in the MM 4550 cluster are proposed based on the results of bioinformatics analysis, gene inactivation, and analysis of disruption mutants. Overall, the differences between the thienamycin and MM 4550 gene clusters are reflected in characteristic structural elements and provide new insights into the biosynthesis of the complex carbapenems.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of the Carbapenem MM 4550 and its Gene Cluster in Streptomyces argenteolus ATCC 11009

Lloyd

Moshos

et al. 2014

ChemBioChem

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“…MM4550 has been related biosynthetically to MM223805) (epithienamycin A), the stereochemistry of which was elucidated as 5-R, 6-R, 8-S6). With respect to the sulfoxide of MM4550, the configuration is inferred to be R from the CD spectrum1) which closely resembles that of C-193937) (carpetimycin) whose structure has been established by X-ray analysis8, 9) As the chromophores of pluracidomycins and MM14550 are different, the direct comparison of Tables 3 and 4*. The details will be reported separately.…”

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The structures of pluracidomycins, new carbapenem antibiotics.

et al. 1982

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Carbapenems and Penems

Southgate

Osborne

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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In the period up to 1970 most β‐lactam research was concerned with the penicillin and cephalosporin group of antibiotics. Since that time, however, a wide variety of new mono‐ and bicyclic β‐lactam structures have been described. The carbapenems originated from natural sources; the penem ring and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are: 7‐oxo‐( R )‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 7 H 7 NO 3 , and 7‐oxo‐( R )‐4‐thia‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 6 H 5 NO 3 S, respectively. Carbapenems include thienamycin (C 11 H 16 N 2 O 4 S), MM 4550 (C 13 H 16 N 2 O 9 S 2 ), MM 13902 (C 13 H 16 N 2 O 8 S 2 ), MM 17880 (C 13 H 18 N 2 O 2 S 2 ), PS‐5 (C 13 H 18 N 2 O 4 S), carpetimycin A (C 14 H 18 N 2 O 6 S), asparenomycin A (C 14 H 16 N 2 O 6 S), and pluracidomycin A (C 9 H 11 NO 10 S 2 ). Only S. cattleya and S. penemfaciens have been reported to give thienamycin. Thienamycin is isolated as a colorless, hygroscopic, zwitterionic solid. Carbapenems are extremely sensitive to many reaction conditions. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure–activity relationships. One consequence of the discovery of the carbapenem natural products has been the development of new synthetic methods. Only chemical synthesis could provide the quantities of N ‐formimidoyl thienamycin (MK 0787) necessary for clinical trials and commercial production. A synthetic approach that involves the [3,4] bond formation using a carbene insertion reaction has been highly successful. A second method makes use of the lactone from acetone dicarboxylate. Thienamycin, the olivanic acids, and the majority of carbapenems are highly active broad‐spectrum antibiotics. Of the natural products, thienamycin is the most potent. Unlike carbapenems, no penems have been found in nature. The penem acid was shown to possess antibacterial activity in spite of its rather limited stability. Penems include SCH 29482 (C 10 H 13 NO 4 S 2 ), SCH 34343 (C 11 H 14 N 2 O 6 S 2 ), FCE 221201 (C 10 H 12 N 2 O 6 S), and others. 6‐Unsubstituted penems exhibit good activity against both gram‐positive and gram‐negative bacteria. Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem–cilastatin combination has become a commercial product. Meropenem was expected to be the second carbapenem on the market.

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Structures and absolute configurations of carpetimycins A and B.

Cited by 32 publications

References 8 publications

Identification and Characterization of the Carbapenem MM 4550 and its Gene Cluster in Streptomyces argenteolus ATCC 11009

Identification and Characterization of the Carbapenem MM 4550 and its Gene Cluster in Streptomyces argenteolus ATCC 11009

The structures of pluracidomycins, new carbapenem antibiotics.

Carbapenems and Penems

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