Triaryl Benzimidazoles as a New Class of Antibacterial Agents against Resistant Pathogenic Microorganisms

A new class of nontoxic
triaryl benzimidazole compounds, derived
from existing classes of DNA minor groove binders, were designed,
synthesized, and evaluated for their antibacterial activity against
multidrug resistant (MDR) Gram-positive and Gram-negative species.
Molecular modeling experiments suggest that the newly synthesized
class cannot be accommodated within the minor groove of DNA due to
a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of
the series, with MICs in the range of 0.5–4 μg/mL against
the MDR Staphylococci and Enterococci species. Compound 13 showed
moderate activity against the MDR Gram-negative strains, with MICs
in the range of 16–32 μg/mL. Active compounds showed
a bactericidal mode of action, and a mechanistic study suggested the
inhibition of bacterial gyrase as the mechanism of action (MOA) of
this chemical class. The MOA was further supported by the molecular
modeling study.