Pentafluorosulfanyl-substituted biaryl derivatives as MATE-type transporter inhibitors targeting drug-resistant bacteria

Multidrug and toxin extrusion (MATE) inhibitors improve the antimicrobial susceptibility of drug-resistant bacteria by preventing the efflux of administered Antibiotics. In this study, we optimized the chemical structure of a previously identified bacterial-selective MATE inhibitor 1 (EC₅₀ > 30 µM) to improve its activity further. Compound 1 was divided into three fragments (aromatic part, linker part, and guanidine part), and each part was individually optimized. Compound 31 (EC₅₀ = 1.8 µM), a novel pentafluorosulfanyl-containing molecule synthesized following optimized parts, showed antimicrobial activity against MATE-expressing strains at concentrations lower than conventional inhibitor 1 when co-administrated with norfloxacin. Furthermore, 31 was not cytotoxic at effective concentrations. This suggests that compound 31 can be a promising candidate for combating Bacterial infections, particularly those resistant to conventional Antibiotics by MATE expression.