Targeting lipoic acid salvage and biosynthesis pathways in MRSA

• Grant number: 17/03966-4
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2018
• End date: May 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Agreement: EU-CELAC IG (former ERA.Net - LAC)
• Principal Investigator: Carsten Wrenger
• Grantee: Carsten Wrenger
• Principal researcher abroad: Bjoern Windshuegel
• Institution abroad: Fraunhofer-Gesellschaft , Germany
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo

Abstract

Infections with methicillin resistant Staphylococcus aureus (MRSA) are a global problem. Besides hospital acquired MRSA, also community associated MRSA strains have emerged that cause skin and soft tissue infections but also life threatening endocarditis and pneumonia. The increasing appearance of multidrug resistants trains urgently requires novel therapeutic approaches in order to keep the drug discovery pipeline filled. This research consortium formed by research groups from Argentina, Brazil, Germany and Latvia aims to identify antibacterial compounds by targeting the lipoic acid metabolism of S. aureus utilising two different approaches: the lipoic acid salvage pathway will be addressed by suicide substrates mimicking natural substrates, resulting in generation of nonfunctional cofactors that poison all cofactor dependent enzymes. A second approach intends to identify enzyme inhibitors targeting lipoic acid biosynthesis enzymes. In order toidentify and optimise molecules targeting lipoic acid salvage and biosynthesis, a rational and integrated approach has been defined utilising a set of complementary techniques (virtual screening, enzymatic and antibacterial assays, medicinal chemistry) and expertises. The results may not only validate enzymes of the lipoic acid biosynthesis and salvage pathway as attractive targets for novel therapeutic approaches, but also provide bioactive molecules for further drug development. (AU)

Scientific publications

(24)

(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)

BOSCH, SORAYA S.; LUNEV, SERGEY; BATISTA, FERNANDO A.; LINZKE, MARLEEN; KRONENBERGER, THALES; DOMLING, ALEXANDER S. S.; GROVES, MATTHEW R.; WRENGER, CARSTEN. Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2. ACS INFECTIOUS DISEASES, v. 6, n. 5, p. 986-999, MAY 8 2020. (17/03966-4, 15/26722-8, 13/17577-9, 14/23330-9)

BATISTA, FERNANDO A.; BOSCH, SORAYA S.; BUTZLOFF, SABINE; LUNEV, SERGEY; MEISSNER, KAMILA A.; LINZKE, MARLEEN; ROMERO, ATILIO R.; WANG, CHAO; MUELLER, INGRID B.; DOMLING, ALEXANDER S. S.; et al. Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum. MICROBIOLOGYOPEN, v. 8, n. 7, JUL 2019. (17/03966-4, 15/26722-8, 16/24790-9, 14/23330-9, 13/17577-9)

SUMAM DE OLIVEIRA, DAFFINY; KRONENBERGER, THALES; PALMISANO, GIUSEPPE; WRENGER, CARSTEN; DE SOUZA, EDMARCIA ELISA. Targeting SUMOylation in Plasmodium as a Potential Target for Malaria Therapy. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, JUN 10 2021. (18/10150-3, 20/04923-0, 19/26771-0, 20/12277-0, 17/03966-4, 18/18257-1, 18/15549-1, 15/26722-8)

DOMBROWSKI, JAMILLE GREGORIO; BARATEIRO, ANDRE; MACHADO PEIXOTO, ERIKA PAULA; CLAUDIO DA SILVA BARROS, ANDRE BOLER; DE SOUZA, RODRIGO MEDEIROS; CLARK, TAANE GREGORY; CAMPINO, SUSANA; WRENGER, CARSTEN; WUNDERLICH, GERHARD; PALMISANO, GIUSEPPE; et al. Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon. PLoS Neglected Tropical Diseases, v. 15, n. 4, APR 2021. (17/03966-4, 17/03939-7, 18/18257-1, 19/12068-5, 15/26722-8, 17/24267-7, 20/06747-4, 18/20468-0, 20/04923-0, 18/15549-1, 17/05782-8)

TAVARES, MAURICIO T.; KRUEGER, ARNE; YAN, SUN L. REI; WAITMAN, KAROLINE B.; GOMES, VINICIUS M.; DE OLIVEIRA, DAFFINY SUMAM; PAZ, FRANCIARLI; HILSCHER, SEBASTIAN; SCHUTKOWSKI, MIKE; SIPPL, WOLFGANG; et al. 1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors. SCIENTIFIC REPORTS, v. 13, n. 1, p. 20-pg., 2023-11-30. (18/08820-0, 18/10150-3, 20/04923-0, 21/00124-8, 18/18257-1, 21/08260-8, 15/26722-8, 18/15549-1, 22/12468-6, 17/26358-0, 21/11606-3, 17/03966-4, 22/07275-4)

BATISTA, FERNANDO A.; GYAU, BENJAMIN; VILACHA, JULIANA F.; BOSCH, SORAYA S.; LUNEV, SERGEY; WRENGER, CARSTEN; GROVES, MATTHEW R.. New directions in antimalarial target validation. EXPERT OPINION ON DRUG DISCOVERY, v. 15, n. 2, p. 189-202, FEB 1 2020. (17/03966-4, 15/26722-8, 13/17577-9)

KRUGER, ARNE; DE JESUS SANTOS, ANA PAULA; DE SA, VANESSA; ULRICH, HENNING; WRENGER, CARSTEN. Aptamer Applications in Emerging Viral Diseases. PHARMACEUTICALS, v. 14, n. 7, JUL 2021. (18/07366-4, 15/26722-8, 17/03966-4, 15/26642-4)

BARRA, ANGELICA LUANA C.; ULLAH, NAJEEB; MORAO, LUANA G.; WRENGER, CARSTEN; BETZEL, CHRISTIAN; NASCIMENTO, ALESSANDRO S.. Structural Dynamics and Perspectives of Vitamin B6 Biosynthesis Enzymes in Plasmodium: Advances and Open Questions. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, JUL 13 2021. (18/21213-6, 19/20219-3, 20/03983-9, 15/13684-0, 19/26428-3, 15/26722-8, 17/03966-4)

FLOREZ-ALVAREZ, LIZDANY; DE SOUZA, EDMARCIA ELISA; BOTOSSO, VIVIANE FONGARO; LEAL DE OLIVEIRA, DANIELLE BRUNA; HO, PAULO LEE; TABORDA, CARLOS PELLESCHI; PALMISANO, GIUSEPPE; CAPURRO, MARGARETH LARA; REBELLO PINHO, JOAO RENATO; FERREIRA, HELENA LAGE; et al. Hemorrhagic fever viruses: Pathogenesis, therapeutics, and emerging and re-emerging potential. FRONTIERS IN MICROBIOLOGY, v. 13, p. 16-pg., 2022-10-25. (16/20045-7, 19/12303-4, 18/18257-1, 20/04923-0, 17/03966-4, 17/27131-9, 22/01812-8, 18/15549-1, 15/26722-8, 20/12277-0, 20/06409-1, 16/08730-6)

LAZARI, LUCAS CARDOSO; GHILARDI, FABIO DE ROSE; ROSA-FERNANDES, LIVIA; ASSIS, DIEGO M.; NICOLAU, JOSE CARLOS; SANTIAGO, VERONICA FEIJOLI; DALCOQUIO, TALIA FALCAO; ANGELI, CLAUDIA B.; BERTOLIN, ADRIADNE JUSTI; MARINHO, CLAUDIO R. F.; et al. Prognostic accuracy of MALDI-TOF mass spectrometric analysis of plasma in COVID-19. LIFE SCIENCE ALLIANCE, v. 4, n. 8, AUG 2021. (20/04705-2, 18/15549-1, 17/03966-4, 15/26722-8, 18/20468-0, 20/04923-0, 18/18257-1)

COUTINHO, JOAO V. P.; ROSA-FERNANDES, LIVIA; MULE, SIMON NGAO; DE OLIVEIRA, GILBERTO SANTOS; MANCHOLA, NUBIA CAROLINA; SANTIAGO, VERONICA FEIJOLI; COLLI, WALTER; WRENGER, CARSTEN; MANSO ALVES, MARIA JULIA; PALMISANO, GIUSEPPE. The thermal proteome stability profile of Trypanosoma cruzi in epimastigote and trypomastigote life stages. JOURNAL OF PROTEOMICS, v. 248, SEP 30 2021. (18/13283-4, 18/15549-1, 14/06863-3, 17/03966-4, 15/26722-8, 17/19854-0, 17/04032-5, 18/18257-1)

LINZKE, MARLEEN; YAN, SUN LIU REI; TARNOK, ATTILA; ULRICH, HENNING; GROVES, MATTHEW R.; WRENGER, CARSTEN. Live and Let Dye: Visualizing the Cellular Compartments of the Malaria Parasite Plasmodium falciparum. Cytometry Part A, v. 97, n. 7, p. 12-pg., 2019-11-18. (17/03966-4, 12/50880-4, 14/23330-9, 12/50393-6, 17/26358-0, 15/26722-8)

LINZKE, MARLEEN; YAN, SUN LIU REI; TARNOK, ATTILA; ULRICH, HENNING; GROVES, MATTHEW R.; WRENGER, CARSTEN. Live and Let Dye: Visualizing the Cellular Compartments of the Malaria Parasite Plasmodium falciparum. Cytometry Part A, v. 97, n. 7, SI, NOV 2019. (12/50880-4, 17/03966-4, 15/26722-8, 14/23330-9, 17/26358-0, 12/50393-6)

GAO, KAI; WANG, WENJIA; KRONENBERGER, THALES; WRENGER, CARSTEN; GROVES, MATTHEW R.. The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation. CRYSTALS, v. 9, n. 10, OCT 2019. (17/03966-4, 14/03644-9, 15/26722-8)

ULLAH, NAJEEB; ANDALEEB, HINA; MUDOGO, CELESTIN NZANZU; FALKE, SVEN; BETZEL, CHRISTIAN; WRENGER, CARSTEN. Solution Structures and Dynamic Assembly of the 24-Meric Plasmodial Pdx1-Pdx2 Complex. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 17, p. 16-pg., 2020-09-01. (17/03966-4, 15/26722-8)

JOHANNSEN, SANDRA; GIERSE, ROBIN M.; KRU''GER, ARNE; EDWARDS, RACHEL L.; NANNA, VITTORIA; FONTANA, ANNA; ZHU, DI; MASINI, TIZIANA; DE CARVALHO, LAIS PESSANHA; POIZAT, MAEL; et al. High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum. ACS INFECTIOUS DISEASES, v. 10, n. 3, p. 23-pg., 2024-02-17. (18/08820-0, 15/26722-8, 17/03966-4, 16/24790-9, 20/12277-0)

MURAD, ALINE MELRO; BROGNARO, HEVILA; FALKE, SVEN; LINDNER, JASMIN; PERBANDT, MARKUS; MUDOGO, CELESTIN; SCHUBERT, ROBIN; WRENGER, CARSTEN; BETZEL, CHRISTIAN. Structure and activity of the DHNA Coenzyme-A Thioesterase from Staphylococcus aureus providing insights for innovative drug development. SCIENTIFIC REPORTS, v. 12, n. 1, p. 14-pg., 2022-03-12. (17/03966-4, 12/12790-3, 15/26722-8)

REI YAN, SUN LIU; WAKASUQUI, FELIPE; DU, XIAOCHEN; GROVES, MATTHEW R.; WRENGER, CARSTEN. Lipoic Acid Metabolism as a Potential Chemotherapeutic Target Against Plasmodium falciparum and Staphylococcus aureus. RONTIERS IN CHEMISTR, v. 9, p. 7-pg., 2021-11-04. (17/26358-0, 15/26722-8, 17/03966-4)

OLIVEIRA, DOUGLAS DAVISON DA SILVA; PAZ, FRANCIARLI; BRITO, NICOLAS PETERSON FERREIRA; KRUGER, ARNE; MARTINHO, ANA CLARA CASSIANO; LAPIERRE, THIBAULT JOSEPH WILLIAM JACQUES DIT; SOUZA, FELIPE DE OLIVEIRA; MALTAROLLO, VINICIUS G.; KRONENBERGER, THALES; MENDES, MARINA SENA; et al. Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 275, p. 16-pg., 2024-06-29. (18/08820-0, 21/13727-2, 15/26722-8, 17/24267-7, 17/03966-4)

GAO, KAI; WANG, WENJIA; KRONENBERGER, THALES; WRENGER, CARSTEN; GROVES, MATTHEW R.. The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation. CRYSTALS, v. 9, n. 10, p. 11-pg., 2019-10-01. (17/03966-4, 14/03644-9, 15/26722-8)

MEISSNER, KAMILA ANNA; KRONENBERGER, THALES; MALTAROLLO, VINICIUS GONCALVES; GOULART TROSSINI, GUSTAVO HENRIQUE; WRENGER, CARSTEN. Targeting the Plasmodium falciparum plasmepsin V by ligand-based virtual screening. CHEMICAL BIOLOGY & DRUG DESIGN, v. 93, n. 3, p. 300-312, MAR 2019. (14/03644-9, 16/24790-9, 17/03966-4, 15/26722-8)

KRUGER, ARNE; ZIMBRES, FLAVIA M.; KRONENBERGER, THALES; WRENGER, CARSTEN. Molecular Modeling Applied to Nucleic Acid-Based Molecule Development. BIOMOLECULES, v. 8, n. 3, SEP 2018. (17/03966-4, 18/08820-0, 15/26722-8)

MORAO, LUANA G.; MANZINE, LIVIA R.; CLEMENTINO, LIVIA OLIVEIRA D.; WRENGER, CARSTEN; NASCIMENTO, ALESSANDRO S.. A scalable screening of E. coli strains for recombinant protein expression. PLoS One, v. 17, n. 7, p. 10-pg., 2022-07-25. (17/24901-8, 17/03966-4, 15/26722-8, 19/20219-3, 20/03983-9)

LAZARI, LUCAS C.; ZERBINATI, RODRIGO M.; ROSA-FERNANDES, LIVIA; SANTIAGO, VERONICA FEIJOLI; ROSA, KLAISE F.; ANGELI, CLAUDIA B.; SCHWAB, GABRIELA; PALMIERI, MICHELLE; SARMENTO, DMITY J. S.; MARINHO, CLAUDIO R. F.; et al. ALDI-TOF mass spectrometry of saliva samples as a prognostic tool for COVID-1. OURNAL OF ORAL MICROBIOLOG, v. 14, n. 1, DEC 31 2022. (18/15549-1, 20/06409-1, 20/04923-0, 18/18257-1, 15/26722-8, 17/03966-4, 21/07490-0, 18/20468-0)