Resumo:
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.
