Structure and activity of the DHNA Coenzyme-A Thioesterase from Staphylococcus aureus providing insights for innovative drug development

Autor(es)

Murad, Aline Melro ; Brognaro, Hevila ; Falke, Sven ; Lindner, Jasmin ; Perbandt, Markus ; Mudogo, Celestin ; Schubert, Robin ; Wrenger, Carsten ; Betzel, Christian

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 12, n. 1, p. 14-pg., 2022-03-12.

Resumo

Humanity is facing an increasing health threat caused by a variety of multidrug resistant bacteria. Within this scenario, Staphylococcus aureus, in particular methicillin resistant S. aureus (MRSA), is responsible for a number of hospital-acquired bacterial infections. The emergence of microbial antibiotic resistance urgently requires the identification of new and innovative strategies to treat antibiotic resistant microorganisms. In this context, structure and function analysis of potential drug targets in metabolic pathways vital for bacteria endurance, such as the vitamin K-2 synthesis pathway, becomes interesting. We have solved and refined the crystal structure of the S. aureus DHNA thioesterase (SaDHNA), a key enzyme in the vitamin K-2 pathway. The crystallographic structure in combination with small angle X-ray solution scattering data revealed a functional tetramer of SaDHNA. Complementary activity assays of SaDHNA indicated a preference for hydrolysing long acyl chains. Site-directed mutagenesis of SaDHNA confirmed the functional importance of Asp16 and Glu31 for thioesterase activity and substrate binding at the putative active site, respectively. Docking studies were performed and rational designed peptides were synthesized and tested for SaDHNA inhibition activity. The high-resolution structure of SaDHNA and complementary information about substrate binding will support future drug discovery and design investigations to inhibit the vitamin K-2 synthesis pathway. (AU)

• Processo FAPESP: 17/03966-4 - Alvejando a via de recuperação e biossíntese de ácido lipoico em MRSA
• Beneficiário: Carsten Wrenger
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/12790-3 - Análise do catabolismo da hemoglobina na proliferação de Plasmodium falciparum em eritrócitos geneticamente modificados
• Beneficiário: Jasmin Lindner
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/26722-8 - Drug discovery contra doenças infecciosas humanos
• Beneficiário: Carsten Wrenger
• Modalidade de apoio: Auxílio à Pesquisa - Temático