Targeting lipoic acid salvage and biosynthesis pathways in MRSA

• Grant number: 17/03966-4
• Support type: Regular Research Grants
• Duration: June 01, 2018 - May 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Cooperation agreement: EU-CELAC IG (former ERA.Net - LAC)
• Principal researcher: Carsten Wrenger
• Grantee: Carsten Wrenger
• Principal researcher abroad: Bjoern Windshuegel
• Institution abroad: Fraunhofer-Gesellschaft, Germany
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

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

(7)

(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. Web of Science Citations: 0.

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. Web of Science Citations: 0.

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. Web of Science Citations: 1.

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. Web of Science Citations: 0.

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.; GROVES, MATTHEW R.; WRENGER, CARSTEN. Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum. MICROBIOLOGYOPEN, v. 8, n. 7 JUL 2019. Web of Science Citations: 1.

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. Web of Science Citations: 2.

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. Web of Science Citations: 4.