Rational design of indolyl acrylamides as antibacterial agents targeting multidrug-resistant Acinetobacter baumannii strains†

Antimicrobial resistance (AMR) has become a significant public health problem. This study investigated the structure–activity relationship of indole core molecules to uncover novel antimicrobials against resistant bacteria. Their antimicrobial evaluation against ESKAPEE bacteria showed superior efficacy compared to cefepime, meropenem, ciprofloxacin, and gentamicin against multidrug-resistant A. baumannii strain A-564, with minimum inhibitory concentration (MIC) values of 4.3 and 1.2 μg mL⁻¹ for compounds 12e and 12j, respectively. Also, the same compounds showed better activity than cefepime for A. baumannii BAA ATCC 747 with MIC values of 1.2 and 4.4 μg mL⁻¹. In addition, 12e and 12f showed activity against methicillin- and penicillin-resistant S. aureus with MIC values of 3.2 and 2.1 μg mL⁻¹. Furthermore, the highly active compounds 12e and 12j exhibited low toxicity, with hemolysis values >40 μg mL⁻¹. Preliminary examination of the mechanism of action revealed that 12e could exhibit dose-dependent inhibition of the AbFtsZ_1–412 enzyme from strain XDR A-564, achieving 51% inhibition of GTPase activity at 32 μg mL⁻¹, thus altering the binary fission process, which could be attributed to the fact that 12e binds to the GTP site and interferes with the function of the enzyme by inhibiting the formation of the Z-ring. Also, a cell viability assay indicates that cells treated with these compounds showed increased permeability, compromising the stability of the A. baumannii A-564 membrane. These results provided valuable information for further developing indolyl-acrylamides as new antimicrobial agents.