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Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism.
Front Microbiol 2019; 10:2550FM

Abstract

Clavulanic acid is a bacterial specialized metabolite, which inhibits certain serine β-lactamases, enzymes that inactivate β-lactam antibiotics to confer resistance. Due to this activity, clavulanic acid is widely used in combination with penicillin and cephalosporin (β-lactam) antibiotics to treat infections caused by β-lactamase-producing bacteria. Clavulanic acid is industrially produced by fermenting Streptomyces clavuligerus, as large-scale chemical synthesis is not commercially feasible. Other than S. clavuligerus, Streptomyces jumonjinensis and Streptomyces katsurahamanus also produce clavulanic acid along with cephamycin C, but information regarding their genome sequences is not available. In addition, the Streptomyces contain many biosynthetic gene clusters thought to be "cryptic," as the specialized metabolites produced by them are not known. Therefore, we sequenced the genomes of S. jumonjinensis and S. katsurahamanus, and examined their metabolomes using untargeted mass spectrometry along with S. clavuligerus for comparison. We analyzed the biosynthetic gene cluster content of the three species to correlate their biosynthetic capacities, by matching them with the specialized metabolites detected in the current study. It was recently reported that S. clavuligerus can produce the plant-associated metabolite naringenin, and we describe more examples of such specialized metabolites in extracts from the three Streptomyces species. Detailed comparisons of the biosynthetic gene clusters involved in clavulanic acid (and cephamycin C) production were also performed, and based on our analyses, we propose the core set of genes responsible for producing this medicinally important metabolite.

Authors+Show Affiliations

Department of Biology, Memorial University of Newfoundland, St. John's, NL, Canada.Department of Biology, Memorial University of Newfoundland, St. John's, NL, Canada.Department of Biology, Memorial University of Newfoundland, St. John's, NL, Canada.Department of Biology, Memorial University of Newfoundland, St. John's, NL, Canada.Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.Department of Biology, Memorial University of Newfoundland, St. John's, NL, Canada.Evolution of Metabolic Diversity Laboratory, Unidad de Genómica Avanzada (Langebio), Cinvestav-IPN, Irapuato, Mexico.Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.Evolution of Metabolic Diversity Laboratory, Unidad de Genómica Avanzada (Langebio), Cinvestav-IPN, Irapuato, Mexico.Department of Biology, Memorial University of Newfoundland, St. John's, NL, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31787949

Citation

AbuSara, Nader F., et al. "Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism." Frontiers in Microbiology, vol. 10, 2019, p. 2550.
AbuSara NF, Piercey BM, Moore MA, et al. Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism. Front Microbiol. 2019;10:2550.
AbuSara, N. F., Piercey, B. M., Moore, M. A., Shaikh, A. A., Nothias, L. F., Srivastava, S. K., ... Tahlan, K. (2019). Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism. Frontiers in Microbiology, 10, p. 2550. doi:10.3389/fmicb.2019.02550.
AbuSara NF, et al. Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism. Front Microbiol. 2019;10:2550. PubMed PMID: 31787949.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism. AU - AbuSara,Nader F, AU - Piercey,Brandon M, AU - Moore,Marcus A, AU - Shaikh,Arshad Ali, AU - Nothias,Louis-Félix, AU - Srivastava,Santosh K, AU - Cruz-Morales,Pablo, AU - Dorrestein,Pieter C, AU - Barona-Gómez,Francisco, AU - Tahlan,Kapil, Y1 - 2019/11/08/ PY - 2019/07/19/received PY - 2019/10/22/accepted PY - 2019/12/3/entrez PY - 2019/12/4/pubmed PY - 2019/12/4/medline KW - Streptomyces KW - clavulanic acid KW - gene clusters KW - genomics KW - metabolomics KW - specialized metabolism KW - β-lactams SP - 2550 EP - 2550 JF - Frontiers in microbiology JO - Front Microbiol VL - 10 N2 - Clavulanic acid is a bacterial specialized metabolite, which inhibits certain serine β-lactamases, enzymes that inactivate β-lactam antibiotics to confer resistance. Due to this activity, clavulanic acid is widely used in combination with penicillin and cephalosporin (β-lactam) antibiotics to treat infections caused by β-lactamase-producing bacteria. Clavulanic acid is industrially produced by fermenting Streptomyces clavuligerus, as large-scale chemical synthesis is not commercially feasible. Other than S. clavuligerus, Streptomyces jumonjinensis and Streptomyces katsurahamanus also produce clavulanic acid along with cephamycin C, but information regarding their genome sequences is not available. In addition, the Streptomyces contain many biosynthetic gene clusters thought to be "cryptic," as the specialized metabolites produced by them are not known. Therefore, we sequenced the genomes of S. jumonjinensis and S. katsurahamanus, and examined their metabolomes using untargeted mass spectrometry along with S. clavuligerus for comparison. We analyzed the biosynthetic gene cluster content of the three species to correlate their biosynthetic capacities, by matching them with the specialized metabolites detected in the current study. It was recently reported that S. clavuligerus can produce the plant-associated metabolite naringenin, and we describe more examples of such specialized metabolites in extracts from the three Streptomyces species. Detailed comparisons of the biosynthetic gene clusters involved in clavulanic acid (and cephamycin C) production were also performed, and based on our analyses, we propose the core set of genes responsible for producing this medicinally important metabolite. SN - 1664-302X UR - https://www.unboundmedicine.com/medline/citation/31787949/Comparative_Genomics_and_Metabolomics_Analyses_of_Clavulanic_Acid-Producing_Streptomyces_Species_Provides_Insight_Into_Specialized_Metabolism L2 - https://doi.org/10.3389/fmicb.2019.02550 DB - PRIME DP - Unbound Medicine ER -