Research Divisions

Biosynthesis of Bioactive Compounds by Microorganisms

Group LeaderLocation and ContactMembersHistory of the GroupLines of ResearchNotable PublicationsProjectsPhD ThesesClinical TrialsPatents and TrademarksNews

María del Carmen Méndez Fernández

  • Professor
  • Functional Biology Department, Universidad de Oviedo
Group leader until july 2020
Prof. José Antonio Salas Fernández ISPA research groups Biosynthesis of Bioactive Compounds
Professor José Antonio Salas Fernández

Professor of Microbiology at the Universidad de Oviedo. After obtaining a degree in Biology and a PhD in Natural Sciences (Biology) at the Universidad de Oviedo, Professor Salas Fernández completed postdoctoral fellowships at the Universities of Cambridge and Leicester (UK).

Upon his return, in collaboration with Professor Carmen Méndez Fernández, he began a line of research on the biosynthesis of secondary metabolites (antibiotics, antitumour agents, etc.) by the microorganisms producing them, which belong to the actinomycete order. This is one of the research areas covered by the Biosynthesis of Bioactive Compounds by Microorganisms (BIOMIC) research group of the Universidad de Oviedo. Since then, several biosynthesis pathways have been isolated and characterised for antibiotics (thienamycin, oleandomycin, streptolydigin), antitumour agents (borrelidin, mithramycin, rebeccamycin, staurosporine, oviedomycin, steffimycin, thiocoraline) and neuroprotectors (collismycin). Through the application of combinatorial biosynthesis and metabolic engineering, over 300 compounds have been generated that contain minor differential modifications of the initial native molecule, some of which have been shown to have promising pharmaceutical properties and have been patented, these patents having been subsequently transferred to biotechnology companies (Biotica, Entrechem).

Founding member of Entrechem S.L., a biotechnology company which is working on developing two antitumour compounds generated by the research group for clinical use. He has supervised 38 PhD theses and is author of 220 publications, including 17 book chapters and reviews and 203 original articles, the vast majority of which are ranked in the top quartile of his research area.

He is co-inventor of a total of 16 patents, 13 of which are international patents that have been licensed and/or are in use by several companies (Hoescht Marion Roussel, Biotica Technology Ltd., Asturpharma S. A., PharmaMar S. A., Entrechem S. L.).

Departamento de Biología Funcional

Facultad de Medicina. Universidad de Oviedo

C/ Julián Claveria s/n. Oviedo, Spain

Telephone: +34 985103652


Name Organisation Activity Euraxess classification
Ceniceros Medrano, Ana Universidad de Oviedo Research R3
Cuervo Del Pozo, Lorena Universidad de Oviedo Research R1
García Gutiérrez, Coral FINBA Research R1
Gómez Malmierca, Mónica Universidad de Oviedo Research R3
González Moreno, María Soledad Universidad de Oviedo Research R1
Méndez Fernández, María Carmen Universidad de Oviedo Research/Teaching R4
Olano Álvarez, Carlos Universidad de Oviedo Research/Teaching R3
Prado Alonso, Laura Universidad de Oviedo Research R1
Rodríguez García, Miriam Universidad de Oviedo Research R2
Salas Fernández, José Antonio Universidad de Oviedo Research/Teaching R3
Peña Noval, Leire Universidad de Oviedo Research No classification

ISPA staff in the Biosynthesis of Bioactive Compounds research group

The group was created approximately 30 years ago by Professors José Antonio Salas and Carmen Méndez. At the beginning, the group’s main interest was in studying the resistance mechanisms which enable bacteria (actinomycetes) that produce antibiotics and other bioactive compounds to survive during the period of producing said compounds, as well as cloning genes for the biosynthesis of bioactive compounds and the characterisation of their biosynthesis pathways. Since it was established, the group has characterised the biosynthesis pathways of several antibiotics (oleandomycin, thienamycin, streptolydigin, caboxamycin, nataxazole and sipanmycin), various antitumour agents (mithramycin, chromomycin, borrelidin, rebeccamycin, staurosporine, oviedomycin, elloramycin, steffimycin, thiocoraline and the macrolide PM100117), a neuroprotector (collismycin) and argimycins P. Using the knowledge about these and other biosynthesis pathways, a new line of research was opened up, consisting of the use of genetic engineering to modify the producer microorganisms, in order to generate new bioactive compounds (combinatorial biosynthesis) and improve their production levels through metabolic engineering. As part of this research, the group has developed several molecular “tools” to modify the glycosylation profiles of the compounds, which have been applied to the generation of new derivatives of antitumour agents such as mithramycin and rebeccamycin. Over the years, the group has generated over 200 new compounds, some of which displayed greater activity and/or lower toxicity than the corresponding natural compounds, and have been patented and licensed to companies. The group’s current priorities are: searching for and characterising new bioactive compounds produced by actinomycetes, by identifying the gene clusters that codify them through genome sequencing (genome mining ); the activation of said biosynthesis pathways, and the generation of new derivatives through combinatorial biosynthesis.

  • Actinomycete genome sequencing and identification of gene clusters for bioactive compounds.
    ISPA Biosynthesis of Bioactive Compounds Research Group, Line of Research 1
    Studying the biosynthesis pathways of bioactive compounds.
  • Activation of “silent” biosynthesis pathways of natural products and identification of new bioactive compounds.
    The activation of silent biosynthesis clusters in actinomycetes enables new bioactive compounds to be obtained.
  • Generation of new bioactive derivatives through combinatorial biosynthesis.
    ISPA Biosynthesis of Bioactive Compounds Research Group, Line of Research 3
    Generation of new derivatives of bioactive compounds.
  1. AUTHORS: Vior, N.M., Olano, C., García, I., Méndez, C. and Salas, J.A. (2014)
    TITLE: Collismycin A biosynthesis in Streptomyces sp. CS40 is regulated by iron levels through two pathway-specific regulators.
    Microbiology 160: 467-478. IF: 2.557. Quartile: Q2
  2. AUTHORS: Olano, C., García, I., González, A., Rodriguez, M., Rozas, D., Rubio, J., Sánchez-Hidalgo, M., Braña, A.F., Méndez, C. and Salas, J.A. (2014)
    TITLE: Activation and identification of five clusters for secondary metabolites in Streptomyces albus J1074.
    Microb. Biotechnol. 7: 242-256. IF: 3.081. Quartile: Q2
  3. AUTHORS: Flórez,A.B., Álvarez, S., Zabala, D., Braña, A.F., Salas, J.A. and Méndez, C. (2015)
    TITLE: Transcriptional regulation of mithramycin biosynthesis in Streptomyces argillaceus: dual role as activator and repressor of the PadR-like regulator MtrY.
    Microbiology 161: 272-284. IF: 2.268. Quartile: Q3
  4. AUTHORS: Cano-Prieto, C., García-Salcedo, R., Sánchez-Hidalgo, M., Braña, A.F., Fiedler, H.P., Méndez, C., Salas, J.A. and Olano, C. (2015)
    TITLE: Crosstalk of nataxazole pathway with chorismate-derived ionophore biosynthesis pathways in Streptomyces sp. Tü 6176
    Chembiochem. Jun 17. doi: 10.1002/cbic.201500261. IF: 2.850. Quartile: Q2
  5. AUTHORS: Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Morales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escribano JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O’Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glöckner FO. (2015)
    TITLE: Minimum information about a biosynthetic gene cluster. JOURNAL: Chemical Communications 53, 9721-9724, 2017.
    Nat Chem Biol. 11: 625-631. IF: 12,709. Quartile: Q1
  6. AUTHORS: Méndez,C., González-Sabín, J., Morís, F., and Salas, J.A. (2015)
    TITLE: Expanding the chemical diversity of the antitumor mithramycin by combinatorial biosynthesis and biocatalysis: the quest for mithralogs with improved therapeutic window.
    Planta Medica 81: 1326-1338. IF: 1.99. Quartile: Q2
  7. AUTHORS: González-Sabín, J., Ríos Lombardía, N., Garcia, I., Miguel Vior, N., Braña, A. F., Mendez, C., Salas, J. A. and Moris, F. (2016)
    TITLE: Laccase-catalysed biotransformation of collismycin derivatives. A novel enzymatic approach for the cleavage of oximes.
    Green Chemistry 18: 989-994. IF: 8.506. Quartile: Q1
  8. AUTHORS: Zabala, D., Braña, A.F., Salas, J.A. and Méndez, C. (2016)
    TITLE: Increasing antibiotic production yields by favoring the biosynthesis of precursor metabolites glucose-1-phosphate and/or malonyl-CoA in Streptomyces producer strains.
    J Antibiot (Tokyo) 69: 179-182. IF: 2.173. Quartile: Q3
  9. AUTHORS: Salcedo, R.G., Olano, C., Gómez, C., Fernández, R., Braña, A.F., Méndez, C., de la Calle, F. and Salas, J.A. (2016)
    TITLE: Characterization and engineering of the biosynthesis gene cluster for antitumor macrolides PM100117 and PM100118 from a marine actinobacteria: generation of a novel improved derivative.
    Microb Cell Fact. Feb 22; 15:44. doi: 10.1186/s12934-016-0443-5. IF: 3.681. Quartile: Q1
  10. AUTHORS: González, A., Rodríguez, M., Braña, A.F., Méndez, C., Salas, J.A. and Olano, C. (2016)
    TITLE: New insights into paulomycin biosynthesis pathway in Streptomyces albus J1074 and generation of novel derivatives by combinatorial biosynthesis.
    Microb Cell Fact. 2016 Mar 21;15:56. doi: 10.1186/s12934-016-0452-4. IF: 3.681. Quartile: Q1
  11. AUTHORS: Salcedo, R.G., Olano, C., Fernández, R., Braña, A.F., Méndez, C., de la Calle, F. and Salas, J.A. (2016)
    TITLE: Elucidation of the glycosylation steps during biosynthesis of antitumor macrolides PM100117 and PM100118 and engineering for novel derivatives.
    Microb Cell Fact. 2016 Nov 9;15(1):187. IF: 3.681. Quartile: Q1
  12. AUTHORS: Ye, S., Molloy, B., Braña, A.F., Zabala, D., Olano, C., Cortés, J., Morís, F., Salas, J.A. and Méndez, C. (2017)
    TITLE: Identification by genome mining of a type I polyketide gene cluster from Streptomyces argillaceus involved in the biosynthesis of pyridine and piperidine alkaloids argimycins P. Front Microbiol. 2017 Feb 10;8:194. doi: 10.3389/fmicb.2017.00194. eCollection 2017. IF: 4.076. Quartile: Q1.
  13. AUTHORS: Losada, A.A., Cano-Prieto, C., García-Salcedo, R., Braña, A.F., Méndez, C., Salas, J.A. and Olano, C. (2017)
    TITLE: Caboxamycin biosynthesis pathway and identification of novel benzoxazoles produced by cross-talk in Streptomyces sp. NTK 937. Microb Biotechnol. 2017 Apr 18. doi: 10.1111/1751-7915.12716. IF: 3.513. Quartile: Q2
  14. AUTHORS: Li,L., Pan, G., Zhu, X., Fan, K., Gao, W., Ai, G., Ren, J., Shi, M., Olano, C., Salas, J.A. and Yang, K. (2017)
    TITLE: Engineered jadomycin analogues with altered sugar moieties revealing JadS as a substrate flexible O-glycosyltransferase.
    Appl. Microbiol. Biotechnol. 2017 Apr 20. doi: 10.1007/s00253-017-8256-y. IF: 3.420. Quartile: Q2
  15. AUTHORS: Hoz, J.F., Méndez, C., Salas, J.A. and Olano, C. (2017)
    TITLE: Novel bioactive paulomycin derivatives produced by Streptomyces albus J1074.
    Molecules. 2017 Oct 18;22(10). pii: E1758. doi: 10.3390/molecules22101758. IF: 2.861. Quartile: Q2
  16. AUTHORS: Losada, A.A., Méndez, C., Salas, J.A. and Olano, C. (2017)
    TITLE: Exploring the biocombinatorial potential of benzoxazoles: generation of novel caboxamycin derivatives.
    Microb Cell Fact. 2017 May 25;16(1):93. doi: 10.1186/s12934-017-0709-6. IF: 3.681. Quartile: Q1
  17. AUTHORS: Malmierca, M.G., González-Montes, L., Pérez-Victoriam I, Sialer, C., Braña, A.F., García Salcedo, R., Martín, J., Reyes, F., Méndez, C., Olano, C. and Salas, J.A. (2018)
    TITLE: Searching for glycosylated natural products in actinomycetes and identification of novel macrolactams and angucyclines.
    Front Microbiol. 2018 Jan 30;9:39. doi: 10.3389/fmicb.2018.00039. IF: 4.076. Quartile: Q1
  18. AUTHORS: Ye,S., Braña, A.F., González-Sabín, J., Morís, F., Olano, C., Salas, J.A. and Méndez. C. (2018)
    TITLE: New insights into the biosynthesis pathway of polyketide alkaloid argimycins P in Streptomyces argillaceus.
    Front Microbiol. 2018 Feb 16;9:252. doi: 10.3389/fmicb.2018.00252. IF: 4.076. Quartile: Q1
  19. AUTHORS: Becerril A, Álvarez S, Braña AF, Rico S, Díaz M, Santamaría RI, Salas JA, Méndez C. (2018)
    TITLE: Uncovering production of specialized metabolites by Streptomyces argillaceus: Activation of cryptic biosynthesis gene clusters using nutritional and genetic approaches.
    PLoS One. May 24;13(5):e0198145. doi: 10.1371/journal.pone.0198145. IF: 2.806. Quartile: Q1
Principal Investigator Title Funding Body Duration Amount
José Antonio Salas Fernández Marine polyketides in oncology. Development of bioprocesses for sourcing antitumour compounds of marine origin through biotechnology MICINN INNPACTO IPT-2011-0752-900000 01-10-2011 to 31-12-2014 €259,310
María Carmen Méndez Fernández Activation and characterisation of the biosynthesis pathways of bioactive compounds in Streptomyces MINECO-15-BIO2014-56752-R 01-01-2015 to 30-06-2018 €217,800
María Carmen Méndez Fernández Application of strategies based on genome sequencing to activate the production of new bioactive compounds in actinomycetes MINECO (BIO2015-64161-R) 01-01-2016 to 31-12-2018 €320,650
José Antonio Salas Fernández Biotechnology applied to the gene desilencing of polyketides and bioactive nonribosomal peptides in marine bacteria (DESPOL) MINECO-RETOS, MINECO-16-RTC-2016-4892-1 07-03-2016 to 31-12-2019 €276,880
María Carmen Méndez Fernández Identification and characterisation of biosynthesis gene clusters of compounds derived from hydroxybenzoates and aminobenzoates in Streptomyces MINECO (BIO2017-82462-R) 01-01-2018 to 31-12-2020 €217,800
PhD Supervisor Supervisors Title Year
Susana Alvarez García José Antonio Salas Fernández
María Carmen Méndez
Identification and analysis of genes for the global regulation of production of the anti-tumour agent mithramycin in Streptomyces argillaceus 2014
Carolina Cano Prieto José Antonio Salas Fernández
Carlos Olano Álvarez
Genome mining in Streptomyces sp. Tü6176 in order to characterise the biosynthesis pathway of the antitumour agent nataxazole 2015
Suhui Ye Huang José Antonio Salas Fernández
María Carmen Méndez
Genome mining of Streptomyces argillaceus: Identification and characterisation of the biosynthesis gene cluster of argimycins 2016
Aránzazu González Bueno José Antonio Salas Fernández
María Carmen Méndez
Identification and analysis of the biosynthesis pathway of paulomycins and its interactions with other gene clusters 2016
Armando Alvarez Losada José Antonio Salas Fernández
Carlos Olano Álvarez
Characterisation of the biosynthesis pathway of the benzoxazole caboxamycin, produced by Streptomyces sp. NTK937 2017
Inventors Title Application No Spanish Patent Date Awarded
Suhui Ye Huang, Brian Molloy Galiana, Alfredo Fernández Braña, Jesús Cortés Bargalló, Francisco Morís Varas, José A. Salas Fernández, M. Carmen Méndez Fernández Argimycin alkaloid compounds produced by Streptomyces argillaceus and their uses P201500825 (18-11-2015) ES2602255 (B1) 20-10-2017