Phenyltriazole-based sulfonamides: novel dual-target agents against MRSA biofilms and resistant pathogens

Abstract

The advent of multidrug-resistant bacteria requires the continuous development of new antimicrobial agents. A series of phenyltriazole–sulfonamide hybrid compounds (16–27) have been synthesized and evaluated for their antimicrobial properties, with a focus on combating resistant bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii AB5075. Compounds were synthesized through a multi-step reaction, including alkylation and aminoguanidine substitution, with structural elucidation performed using NMR and elemental analysis. Antimicrobial activity was assessed through Minimum Inhibitory Concentration (MIC) measurements, which revealed that compounds with longer alkyl chains or specific functional groups had a very enhanced activity against MRSA, especially 23 and 24 analogs. The results highlighted the correlation between lipophilicity (log P) and antimicrobial efficacy, particularly for compounds such as 23 (n-nonyl) which showed potent activity against MRSA. Further evaluation by time-killing assays demonstrated the rapid bactericidal activity of compound 23, while biofilm disruption studies showed the potential of these compounds to target biofilm-associated infections. Docking studies have shown that these compounds can interact with key bacterial targets, including PBP2a and DHPS, providing a dual-target approach for treatment of MRSA. Furthermore, in silico analysis revealed favorable pharmacokinetic and ADME properties of the synthesized compounds. The study shows promising new candidates for combating antimicrobial resistance, with the potential for further optimization and development.