Identificação de inibidores de estafiloxantina em Staphylococcus Aureus e sua interação com carvacrol

Abstract

Bacterial resistance to antimicrobials represents a serious threat to global public health, urgently requiring new therapeutic alternatives. A promising approach is the modulation of bacterial virulence factors, which do not affect cell viability, as they exert less evolutionary pressure and can be used in combination with drugs whose efficacy is compromised. Staphylococcus aureus, a Gram-positive bacterium with a high degree of resistance, produces several virulence factors, among which staphyloxanthin (STX) and biofilm stand out. Objective: To identify inhibitors of STX production in S. aureus that exhibit a synergistic or additive effect with carvacrol, without affecting the cell viability of this pathogen. Methodology: Cell assays were performed to screen 35 substances from different chemical classes for their activity on cell viability. Compounds that did not affect cell viability at a concentration of 100 µM were evaluated for their effect on STX production using Raman spectroscopy. The most promising compounds had their EC50 determined and were subsequently evaluated for their effect on biofilm formation, S. aureus survival in the presence of H²O², and in combination with carvacrol (checkerboard method). Results: Ten substances containing the imidazopyridine or fatlimidine scaffold were identified assignificantly inhibiting STX production at a concentration of 100 µM. The most potent compound (QHM 827) presented an EC50 of 14.7 ± 0.93 µM and significantly reduced (p < 0.05) the survival of S. aureus in the presence of H²O² but did not affect (p > 0.05) biofilm formation at a concentration of 100 µM. The combination of QHM 827 with carvacrol demonstrated a significant synergistic effect (FICI ≤ 5) at concentrations of 1.56-12.5 µM for QHM 827 and 2.5-1.25 µM for carvacrol. Conclusion: Imidazopyridine derivatives are promising inhibitors of STX production in S. aureus, which, in combination with carvacrol, reduce the cell viability of this pathogen through mechanisms not yet fully established.