Development of Bis-cyclic Imidazolidine-4-one Derivatives as Potent Antibacterial Agents

Antibiotic
resistance has emerged as one of the biggest public
health concerns all over the world. In an effort to combat bacterial
infections, a series of imidazolidine-4-one derivatives with potent
and broad-spectrum antibacterial activity and low rates of drug resistance
were developed by mimicking the salient physiochemical features of
host defense peptides. These small molecules displayed potent activity
against both Gram-negative and Gram-positive bacteria including several
multidrug-resistant bacteria strains. Meanwhile, time–kill
kinetics and drug resistance studies suggested that the most potent
compound 3 could not only eliminate the bacteria rapidly
but also exhibit a low probability of drug resistance in MRSA over
many passages. Further mechanistic studies suggested that 3 eradicated bacterial pathogens by disintegrating membranes of both
Gram-negative and Gram-positive bacteria. Together with their small
molecular weight and low production cost compared with HDPs, these
imidazolidine-4-one compounds may be developed into a new generation
of antibiotic therapeutics combating emergent drug resistance.