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Production and purification of clavulanic acid, cephamycin C and other bioactive metabolites of Streptomyces

Abstract

The project deals with the investigation of the necessary steps to develop biotechnology for the production of bioactive substances obtained from Streptomyces. For clavulanic acid, AC and cephamycin C, CefC the study intends to fully develop complete production process alternatives including: genetic improvement, bioprocess, and bioreactor development, and also downstream processes development (separation, extraction and purification). Analysis, modeling and simulation of the whole system, as well as of each one ofthe steps, will be performed. The Technology to be generated will be made available for commercial exploitation, under license. The results obtained for these molecules will be applied to the other bioactive compounds isolated. For (4) research institutions will be directly and actively involved in this task: IQ/Unesp Araraquara, (Institute of Chemistry, UNESP) with emphasis on genetic improvement and on isolation and characterization of new bioactive compounds; Agrupamento de Biotecnologia, AB, do IPT, São Paulo, (Biotechnology Group, Institute for Technological Research) researchers will participate more actively in the steps involving mutants characterization, scale-up of the bioreactors in the fermentation process and in the evaluation of anti-tumor ability of the extracts from Streptomyces cultivation. FEA/Unicamp, Campinas, (Faculty of Food Engineering, Unicamp) researchers will participate in the steps concerning operations of separation and purification, with emphasis on utilization of zeolites, as molecular sieve, and nanofiltration; and DEQ/UFSCar, São Carlos, (Department of Chemical Engineering, UFSCar) members, including the project coordinator, will concentrate activities on conventional and non-conventional bioprocess and bioreactor development, such as airlift bioreactor development for AC and CefC production in batch, fed-batch and continuous, with and without cell recycle, processes. Also, with the same emphasis, separation, purification and characterization of biomolecules will be studied. Besides, the Department of Chemistry, UFSCar, ( Departamento de Química da UFSCar), will participate, initially making available equipments for Instrumental Analysis to identify beta-lactam compounds. The main equipments are, Nuclear Magnetic Ressonance, NMR, from the laboratory of Prof. Antonio Gilberto Ferreira and Mass Spectrometry, MS, coupled with HPLC, from the laboratory of Prof. Edson Rodrigues Filho; later, works in collaboration will be accomplished to identify and characterize new bioactive molecules isolated from streptomycetes. In this phase, the Institute of Chemistry, Unesp (IQ Unesp) will also provide expertise in instrumental analysis, offering services for analysis and characterization of bioactive molecules. Mention should be made that, besides the wild strain, Streptomyces clavuligerus ATCC 27064, additional for (4) Streptomyces strains, isolated from marine sediments, one of them considered a new species, are available, at our laboratory, to search for new bioactive compounds. Furthermore, both, Prof. José C. Menezes, from ISTL - Instituto Superior Técnico de Lisboa - expert in Control of Bioprocess, with major experience in AC industrial production process by S. clavuligerus; and Prof.a. Paloma Liras from Faculty of Biology, University of León, Spain, expert in biosynthesis and molecular genetics of beta-lactam antibiotics, including AC and CefC from S. clavuligerus, already agreed to collaborate with us in the present project, exchanging visits and receiving researchers and students in their laboratory to develop specific studies. (AU)

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Scientific publications (34)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DOMINGUES‚ L.C.G.; TEODORO‚ J.C.; HOKKA‚ C.O.; BADINO‚ A.C.; ARAUJO‚ M.L.G.C.. Optimisation of the glycerol-to-ornithine molar ratio in the feed medium for the continuous production of clavulanic acid by Streptomyces clavuligerus. Biochemical Engineering Journal, v. 53, n. 1, p. 7-11, . (05/55079-4)
CERRI‚ M.O.; BALDACIN‚ J.C.; CRUZ‚ A.J.G.; HOKKA‚ C.O.; BADINO‚ A.C.. Prediction of mean bubble size in pneumatic reactors. Biochemical Engineering Journal, v. 53, n. 1, p. 12-17, . (05/55079-4)
CAMPESI, ALEXANDRE; CERRI, MARCEL O.; HOKKA, CARLOS O.; BADINO, ALBERTO C.. Determination of the average shear rate in a stirred and aerated tank bioreactor. Bioprocess and Biosystems Engineering, v. 32, n. 2, p. 241-248, . (05/55079-4)
PRISCILA RATTI, R.; TOLEDO PIZA, A. C. M.; GRANATO, A. C.; HOKKA, C. O.; PAIVA DE SOUSA, C.; MENDEZVILAS, A. Isolation and antimicrobial activity of Streptomyces tubercidicus against pathogenic bacteria and fungi. MICROORGANISMS IN INDUSTRY AND ENVIRONMENT: FROM SCIENTIFIC AND INDUSTRIAL RESEARCH TO CONSUMER PRODUCTS, v. N/A, p. 3-pg., . (05/55079-4)
PRISCILA RATTI, R.; TOLEDO PIZA, A. C. M.; GRANATO, A. C.; HOKKA, C. O.; DUBREUIL, J. D.; PAIVA DE SOUSA, C.; MENDEZVILAS, A. Growing kinetics and antimicrobial activity of Streptomyces tubercidicus crude extracts. MICROORGANISMS IN INDUSTRY AND ENVIRONMENT: FROM SCIENTIFIC AND INDUSTRIAL RESEARCH TO CONSUMER PRODUCTS, v. N/A, p. 4-pg., . (05/55079-4)
YOUSSEF RODRIGUEZ, G.; SACARDO DA SILVA, C.; OSAMU HOKKA, C.; BARBOZA, M.; MENDEZVILAS, A. Extraction of clavulanic acid in aqueous two-phase systems followed by separation through ultrafiltration. MICROORGANISMS IN INDUSTRY AND ENVIRONMENT: FROM SCIENTIFIC AND INDUSTRIAL RESEARCH TO CONSUMER PRODUCTS, v. N/A, p. 5-pg., . (09/03551-2, 05/55079-4)
ALMEIDA, RENATA M. R. G.; PASOTTO, MARLEI B.; HOKKA, CARLOS O.; MENDEZVILAS, A. Optimization of the continuous clavulanic acid adsorption process. MICROORGANISMS IN INDUSTRY AND ENVIRONMENT: FROM SCIENTIFIC AND INDUSTRIAL RESEARCH TO CONSUMER PRODUCTS, v. N/A, p. 6-pg., . (05/55079-4)
GRANATO, ANA CLAUDIA; ROMANO, LUIS H.; OLIVEIRA, JAINE H. H. L.; RATTI, REGIANE P.; HERNANDEZ, ISARA L. C.; MONTENEGRO, RAQUEL C.; BARBOZA, MARLEI; SOUZA, CRISTINA P.; HOKKA, CARLOS O.; TRSIC, MILAN; et al. Chemical and pharmacological study of Brazilian marine Streptomyces. MICROORGANISMS IN INDUSTRY AND ENVIRONMENT: FROM SCIENTIFIC AND INDUSTRIAL RESEARCH TO CONSUMER PRODUCTS, v. N/A, p. 5-pg., . (05/55079-4)
CERRI, MARCEL OTAVIO; POLICARPO, LUCAS MAKRAKIS; BADINO, ALBERTO COLLI. Gas Hold-Up and Mass Transfer in Three Geometrically Similar Internal Loop Airlift Reactors Using Newtonian Fluids. INTERNATIONAL JOURNAL OF CHEMICAL REACTOR ENGINEERING, v. 8, p. 24-pg., . (08/10432-7, 05/55079-4)
SOUSA, C. P.; CRUZ-HERNANDEZ, I. L.; BAPTISTA-NETO, A.; TEODORO, J. C.; CERRI, M.; ORTIZ, S. C. A.; FREITAS, T. L.; ARAUJO, M. L. G. C.; BADINO, A. C.; HOKKA, C. O.; et al. Challenges attending upon studies on clavulanic acid production. CURRENT RESEARCH TOPICS IN APPLIED MICROBIOLOGY AND MICROBIAL BIOTECHNOLOGY, v. N/A, p. 2-pg., . (05/55079-4)
BRITES, L. M.; OLIVEIRA, J. H.; BARBOZA, M.; HOKKA, C. O.. EFFECT OF PHYSICOCHEMICAL PROPERTIES OF SOLVENTS ON CLAVULANIC ACID EXTRACTION FROM FERMENTATION BROTH. LATIN AMERICAN APPLIED RESEARCH, v. 42, n. 1, p. 65-70, . (05/55079-4)
JAINE H. H. LUIZ DE OLIVEIRA; ANA CLAUDIA GRANATO; DANIELA B. HIRATA; CARLOS O. HOKKA; MARLEI BARBOZA; MILAN TRSIC. Ácido clavulânico e cefamicina c: uma perspectiva da biossíntese, processos de isolamento e mecanismo de ação. Química Nova, v. 32, n. 8, p. 2142-2150, . (05/55079-4)
TEODORO, J. C.; BAPTISTA-NETO, A.; ARAUJO, M. L. G. C.; HOKKA, C. O.; BADINO, A. C.. Influence of glycerol and ornithine feeding on clavulanic acid production by Streptomyces clavuligerus. Brazilian Journal of Chemical Engineering, v. 27, n. 4, p. 499-506, . (05/55079-4)
CERRI, M. O.; FUTIWAKI, L.; JESUS, C. D. F.; CRUZ, A. J. G.; BADINO, A. C.. Average shear rate for non-Newtonian fluids in a concentric-tube airlift bioreactor. Biochemical Engineering Journal, v. 39, n. 1, p. 51-57, . (05/55079-4)
ANTONIO, TATIANA; BELLAO, CAROLINA; CORREA, TATIANA; CAVALLIERI, ANDRE PASTRELO; BADINO, ALBERTO COLLI; GONSALES DA COSTA ARAUJO, MARIA LUCIA. Evaluation of Different Media for the Production of Cephalosporins by Streptomyces clavuligerus ATCC 27064. Brazilian Archives of Biology and Technology, v. 55, n. 6, p. 819-825, . (08/03579-1, 05/55079-4)
HIRATA, D. BATTAGLIA; HORTOLAN LUIZ DE OLIVEIRA, J. H.; FERREIRA, A. G.; LEAO, K. VELOSO; SOUSA, C. P.; BARBOZA, M.; HOKKA, C. OSAMU; MENDEZVILAS, A. Preparation of clavulanate salt using a tertiary octylamine as an intermediate. CURRENT RESEARCH TOPICS IN APPLIED MICROBIOLOGY AND MICROBIAL BIOTECHNOLOGY, v. N/A, p. 2-pg., . (05/55079-4)
CUEL, MARESSA; BARBOZA, MARLEI; HOKKA, CARLOS; KWONG, WU. A Sequencing Method Applied to the Solution of a Linear Model of an Adsorption Column. CHEMICAL PRODUCT AND PROCESS MODELING, v. 4, n. 4, p. 15-pg., . (05/55079-4)
DE OLIVEIRA, LILIANE MACIEL; BARBOZA, MARLEI; IEEE. Separation of cephalosporins using ionic and neutral polimeric resins. 2012 IEEE 2ND PORTUGUESE MEETING IN BIOENGINEERING (ENBENG), v. N/A, p. 5-pg., . (05/55079-4)
RATTI, R. P.; GRANATO, A. C.; HOKKA, C. O.; BADINO-JUNIOR, A. C.; LIMA, L. C. P. S.; PAIVA DE SOUSA, C.; MENDEZVILAS, A. Endophytic Streptomyces tubercidicus isolated from Solanun lycocarpum St Hill: A sheriff secondary metabolites producer. MICROBES IN APPLIED RESEARCH: CURRENT ADVANCES AND CHALLENGES, v. N/A, p. 5-pg., . (05/55079-4)
GRANATO, ANA CLAUDIA; COSTAE, EDSON B.; BARBOZA, MARLEI; TRSIC, MILAN; MENDEZVILAS, A. Structure activity relationship study of the beta-lactamase inhibitors and theoretical design for new bioactive compounds. MICROORGANISMS IN INDUSTRY AND ENVIRONMENT: FROM SCIENTIFIC AND INDUSTRIAL RESEARCH TO CONSUMER PRODUCTS, v. N/A, p. 6-pg., . (05/55079-4)
TOLEDO PIZA, A. C. M.; PRISCILA RATTI, R.; SERRANO, N. F. G.; HOKKA, C. O.; DUBREUIL, J. DANIEL; PAIVA DE SOUSA, C.; MENDEZVILAS, A. Isolation, phenogenotypic idenfication and bioactivity evaluation of endophytic microorganisms intrinsically associated with Miconia albicans in Brazilian tropical savannah tree in Sao Carlos, SP. MICROORGANISMS IN INDUSTRY AND ENVIRONMENT: FROM SCIENTIFIC AND INDUSTRIAL RESEARCH TO CONSUMER PRODUCTS, v. N/A, p. 4-pg., . (05/55079-4)
CUEL, MARESSA; BARBOZA, MARLEI; HOKKA, CARLOS; KWONG, WU. Heterogeneous Model of the Process of Clavulanic Acid Purification by Ionic Exchange in a Fixed-Bed Column. CHEMICAL PRODUCT AND PROCESS MODELING, v. 6, n. 1, p. 19-pg., . (05/55079-4)
ANA C. GRANATO; EDSON B. COSTA; WAGNER F. D. ANGELOTTI; GEOFFROY R. P. MALPASS; MARLEI BARBOZA; ALBÉRICO B. F. DA SILVA; MILAN TRSIC. PRECIPITATION REACTION OF CLAVULANIC ACID: THERMODYNAMIC AND ELECTRONIC STUDY. Química Nova, v. 39, n. 8, p. 968-972, . (05/55079-4)
LEITE, CARLA A.; CAVALLIERI, ANDRE P.; BAPTISTA, AMANDA S.; ARAUJO, MARIA L. G. C.. Dissociation of cephamycin C and clavulanic acid biosynthesis by 1,3-diaminopropane in Streptomyces clavuligerus. FEMS Microbiology Letters, v. 363, n. 1, . (12/22181-4, 13/02632-4, 05/55079-4)
C. BELLÃO; T. ANTONIO; M. L. G. C. ARAUJO; A. C. BADINO. Production of clavulanic acid and cephamycin C by Streptomyces clavuligerus under different fed-batch conditions. Brazilian Journal of Chemical Engineering, v. 30, n. 2, p. 257-266, . (11/23807-1, 05/55079-4)
GRANATO, A. C.; BARBOZA, M.; ROMANO, L. H.; HERNANDEZ, I. L. C.; HOKKA, C. O.; OLIVEIRA, J. H. H. L.; MONTENEGRO, R. C.; DE SOUSA, C. P.. Comparison of growth methods and biological activities of brazilian marine Streptomyces. Brazilian Journal of Chemical Engineering, v. 30, n. 1, p. 125-131, . (05/55079-4)
CERRI, M. O.; BADINO, A. C.. Oxygen transfer in three scales of concentric tube airlift bioreactors. Biochemical Engineering Journal, v. 51, n. 1-2, p. 40-47, . (05/55079-4, 08/10432-7)
DE BAPTISTA NETO, ALVARO; CONDORI BUSTAMANTE, MARITZA CATALINA; HORTOLAN LUIZ DE OLIVEIRA, JAINE HONORATA; GRANATO, ANA CLAUDIA; BELLAO, CAROLINA; BADINO JUNIOR, ALBERTO COLLI; BARBOZA, MARLEI; HOKKA, CARLOS OSAMU. Preliminary Studies for Cephamycin C Purification Technique. Applied Biochemistry and Biotechnology, v. 166, n. 1, p. 208-221, . (05/55079-4)
THOMASI, SERGIO S.; CERRI, MARCEL O.; BADINO, ALBERTO C.. Average shear rate in three pneumatic bioreactors. Bioprocess and Biosystems Engineering, v. 33, n. 8, p. 979-988, . (05/55079-4, 08/10432-7)
DA SILVA, CLOVIS SACARDO; CUEL, MARESSA FABIANO; BARRETO, VERONICA ORLANDIN; KWONG, WU HONG; HOKKA, CARLOS O.; BARBOZA, M.. Separation of clavulanic acid from fermented broth of amino acids by an aqueous two-phase system and ion-exchange adsorption. NEW BIOTECHNOLOGY, v. 29, n. 3, p. 428-431, . (05/55079-4)
LEITE, CARLA A.; CAVALLIERI, ANDRE P.; ARAUJO, MARIA L. G. C.. Enhancing effect of lysine combined with other compounds on cephamycin C production in Streptomyces clavuligerus. BMC Microbiology, v. 13, . (13/02632-4, 05/55079-4)
BRITES, LUCIANA M.; OLIVEIRA, LILIANE M.; BARBOZA, MARLEI. Kinetic Study on Cephamycin C Degradation. Applied Biochemistry and Biotechnology, v. 171, n. 8, p. 2121-2128, . (05/55079-4)
CERRI, MARCEL OTAVIO; POLICARPO, LUCAS MAKRAKIS; BADINO, ALBERTO COLLI. Gas Hold-Up and Mass Transfer in Three Geometrically Similar Internal Loop Airlift Reactors Using Newtonian Fluids. International Journal of Chemical Reactor Engineering, v. 8, . (08/10432-7, 05/55079-4)
SILVA, C. S.; BOVAROTTI, E.; RODRIGUES, M. I.; HOKKA, C. O.; BARBOZA, MARLEI. Evaluation of the effects of the parameters involved in the purification of clavulanic acid from fermentation broth by aqueous two-phase systems. Bioprocess and Biosystems Engineering, v. 32, n. 5, p. 625-632, . (05/55079-4)

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Filed patent(s) as a result of this research project

PROCESSO PARA EXTRAÇÃO E PURIFICAÇÃO DE ÁCIDO CLAVULÂNICO, SEUS SAIS E ÉSTERES PI0704995-1 - Universidade Federal de São Carlos (UFSCAR) . Marlei Barboza Pasotto ; Carlos Osamu Hokka ; Alberto Colli Badino Junior ; Clóvis Saccardo Da Silva ; Verônica Orlandin Barreto ; Jaine Oliveira H. Ortalan Luiz De Oliveira ; Gulherme Youssef Rodrigues ; Juliana Conceição Teodoro ; Sheila Cristiane Alves Ortiz ; Álvaro Batista Netto ; Daniela Bataglia Hirata ; Marcel Otavio Cerri - December 2007, 26