Efeito sinérgico de derivados de ácido fenazina-1 carboxílico com AgNO3 sobre a produção de piocianina ou como ligantes de PhzS frente Pseudomonas aeruginosa

Abstract

Bacterial resistance to antibiotics is a serious threat to global public health. With the reduction in investments aimed at developing new classical antibacterials, strategies focused on creating anti-virulence compounds have emerged as promising alternatives. In this context, enzymes responsible for the biosynthesis of pyocyanin (PYO) — a phenazine pigment produced by 90-95% of clinical isolates of Pseudomonas aeruginosa — are potential targets for the development of new drugs. This study aims to evaluate whether phenazine carboxylic acid (PCA) derivatives bind to the PhzS enzyme and/or inhibit PYO production. In phenotypic assays, a PCA derivative (HD09) containing indole in its chemical structure was identified, which reduces pyocyanin production by approximately 30% without affecting cell growth. However, this compound demonstrated stimulation of biofilm production in P. aeruginosa. Despite not affecting the phenotypic production of PYO, PCA derivatives of the SQXA class were identified as PhzS ligands by the thermostability assay (TSA), with SQXA14 showing micromolar affinity for the enzyme, binding through a competitive mechanism with PCA (PhzS substrate). Additionally, the effect of this compound combined with silver nitrate was evaluated. According to the Checkerboard assay, there is a synergistic effect on the inhibition of PYO production in P. aeruginosa. Therefore, this study suggests that PCA derivatives should be combined with other bactericidal and/or bacteriostatic agents to significantly reduce PYO production.