| Texto completo | |
| Autor(es): |
Cabrera, Vitoria Isabela Montanhero
;
Sividanes, Gabrielle do Nascimento
;
Quintiliano, Natalia Fernanda
;
Toyama, Marcos Hikari
;
Lago, Joao Henrique Ghilardi
;
de Oliveira, Marcos Antonio
Número total de Autores: 6
|
| Tipo de documento: | Artigo Científico |
| Fonte: | PLoS One; v. 18, n. 2, p. 21-pg., 2023-02-24. |
| Resumo | |
Multiple drug resistance (MDR) bacterial strains are responsible by 1.2 million of human deaths all over the world. The pathogens possess efficient enzymes which are able to mitigate the toxicity of reactive oxygen species (ROS) produced by some antibiotics and the host immune cells. Among them, the bacterial peroxiredoxin alkyl hydroperoxide reductase C (AhpC) is able to decompose efficiently several kinds of hydroperoxides. To decompose their substrates AhpC use a reactive cysteine residue (peroxidatic cysteine-Cys(P)) that together with two other polar residues (Thr/Ser and Arg) comprise the catalytic triad of these enzymes and are involved in the substrate targeting/stabilization to allow a bimolecular nucleophilic substitution (S(N)2) reaction. Additionally to the high efficiency the AhpC is very abundant in the cells and present virulent properties in some bacterial species. Despite the importance of AhpC in bacteria, few studies aimed at using natural compounds as inhibitors of this class of enzymes. Some natural products were identified as human isoforms, presenting as common characteristics a bulk hydrophobic moiety and an alpha, beta-unsaturated carbonylic system able to perform a thiol-Michael reaction. In this work, we evaluated two chemically related natural products: 1,4-dihydroxy-2-(3',7'-dimethyl-1'-oxo-2'E,6'-octadienyl) benzene (C1) and 4-hydroxy-2-(3',7'-dimethyl-1'-oxo-2'E,6'-octadienyl) benzoic acid (C2), both were isolated from branches Piper crassinervium (Piperaceae), over the peroxidase activity of AhpC from Pseudomonas aeruginosa (PaAhpC) and Staphylococcus epidermidis (SeAhpC). By biochemical assays we show that although both compounds can perform the Michael addition reaction, only compound C2 was able to inhibit the PaAhpC peroxidase activity but not SeAhpC, presenting IC50 = 20.3 mu M. SDS-PAGE analysis revealed that the compound was not able to perform a thiol-Michael addition, suggesting another inhibition behavior. Using computer-assisted simulations, we also show that an acidic group present in the structure of compound C2 may be involved in the stabilization by polar interactions with the Thr and Arg residues from the catalytic triad and several apolar interactions with hydrophobic residues. Finally, C2 was not able to interfere in the peroxidase activity of the isoform Prx2 from humans or even the thiol proteins of the Trx reducing system from Escherichia coli (EcTrx and EcTrxR), indicating specificity for P. aeruginosa AhpC. (AU) | |
| Processo FAPESP: | 20/02868-1 - Efeitos compostos naturais sobre a atividade peroxidásica de AhpCs e sobrevivência de bactérias patogênicas |
| Beneficiário: | Vitória Isabela Montanhero Cabrera |
| Modalidade de apoio: | Bolsas no Brasil - Mestrado |
| Processo FAPESP: | 13/07937-8 - Redoxoma |
| Beneficiário: | Ohara Augusto |
| Modalidade de apoio: | Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs |
| Processo FAPESP: | 17/19942-7 - Busca de inibidores do sistema peroxirredoxina de patógenos e humanos |
| Beneficiário: | Marcos Antonio de Oliveira |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 21/02789-7 - Busca de metabólitos bioativos com ação antiparasitária em espécies vegetais de regiões de Mata Atlântica e Cerrado - uma abordagem química, fenotípica e metabolômica |
| Beneficiário: | João Henrique Ghilardi Lago |
| Modalidade de apoio: | Auxílio à Pesquisa - Programa BIOTA - Regular |
| Processo FAPESP: | 17/20291-0 - Caracterização da atividade pró-inflamatória de uma nova serino protease (cdtsp-2) purificada do veneno total de Crotalus durissus terrificus |
| Beneficiário: | Marcos Hikari Toyama |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |