Escaping ESKAPE resistance: In vitro and in silico studies of multifunctional carbamimidoyl-tethered indoles against antibiotic-resistant bacteria

Combining the hybridization and repurposing strategies, six compounds from our in-house library with a designed hybrid structure of MBX-1162, pentamidine and MMV688271 were repurposed as potential antibacterial agents. Amongst them, compounds 1a and 1d elicited potential sub-µg/mL activity against the high-priority antibiotic-resistant Gram-positive members of ESKAPE bacteria as well as antibiotic-susceptible Gram-positive bacteria. Furthermore, they showed potential low µg/mL activity against the explored critical priority antibiotic-resistant Gram-negative members of ESKAPE bacteria. In time-kill assay, compound 1a has effective 0.5 and 0.25 µg/mL antibacterial lethal concentrations against MRSA in the exponential growth phase. In silico investigations predicted compounds 1a and 1d as inhibitors of the open conformation of undecaprenyl diphosphate synthase involved in bacterial isoprenoid synthesis. In addition, compounds 1a and 1d were predicted as inhibitors of the NADPH-free but not the NADPH-bound form of ketol-acid reductoisomerase and may also serve as potential B-DNA minor groove binders with possible differences in the molecular sequence recognition. Overall, compounds 1a and 1d are presented as multifunctional potential antibacterial agents for further development against high and critical-priority Gram-positive and Gram-negative antibiotic-resistant ESKAPE bacterial pathogens as well as antibiotic-susceptible Gram-positive bacterial pathogens.