Membrane-Active Hydantoin Derivatives as Antibiotic Agents

Hydantoin
(imidazolidinedione) derivatives such as nitrofurantoin
are small molecules that have aroused considerable interest recently
due to their low rate of bacterial resistance. However, their moderate
antimicrobial activity may hamper their application combating antibiotic
resistance in the long run. Herein, we report the design of bacterial
membrane-active hydantoin derivatives, from which we identified compounds
that show much more potent antimicrobial activity than nitrofurantoin
against a panel of clinically relevant Gram-positive and Gram-negative
bacterial strains. These compounds are able to act on bacterial membranes,
analogous to natural host-defense peptides. Additionally, these hydantoin
compounds not only kill bacterial pathogens rapidly but also prevent
the development of methicillin-resistant Staphylococcus
aureus (MRSA) bacterial resistance under the tested
conditions. More intriguingly, the lead compound exhibited in vivo efficacy that is much superior to vancomycin by
eradicating bacteria and suppressing inflammation caused by MRSA-induced
pneumonia in a rat model, demonstrating its promising therapeutic
potential.