Antibiofilm effects of N,O-acetals derived from 2-amino-1,4-naphthoquinone are associated with downregulation of important global virulence regulators in methicillin-resistant Staphylococcus aureus

Despite the existing antibiotics, antimicrobial resistance is a major challenge. Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study was to evaluate the antibiofilm activities of synthetic N , O -acetals derived from 2-amino-1,4-naphthoquinone [ 7a : 2-(methoxymethyl)-amino-1,4-naphthoquinone; 7b : 2-(ethoxymethyl)-amino-1,4-naphthoquinone; and 7c : 2-(propynyloxymethyl)-amino-1,4-naphthoquinone] against methicillin-resistant Staphylococcus aureus (MRSA). The derivatives 7b and 7c , specially 7b , caused strong impact on biofilm accumulation. This inhibition was linked to decreased expression of the genes fnbA , spa , hla and psmα3 . More importantly, this downregulation was paralleled by the modulation of global virulence regulators. The substitution of 2-ethoxymethyl ( 7b ) in comparison with 2-propynyloxymethyl ( 7c ) enhanced sarA - agr inhibition, decreased fnbA transcripts (positively regulated by sarA ) and strongly impaired biofilm accumulation. Indeed, 7b triggered intensive autolysis and was able to eliminate vancomycin-persistent cells. Consequently, 7b is a promising molecule displaying not only antimicrobial effects, but also antibiofilm and antipersistence activities. Therefore, 7b is a good candidate for further studies involving the development of novel and more rational antimicrobials able to act in chronic and recalcitrant infections, associated with biofilm formation.