Prevalence of drug-resistant bacteria has emerged to be one of the greatest threats in the 21<sup>st</sup> century. Accelerated loss of efficacy in conventional antibiotics leads to significant interest in the development of antibiotic agents with novel mechanisms. Although long peptides containing reduced amide moiety have been reported for antimicrobial activity, small molecules of the similar type are not yet investigated. Herein, we report the development of a series of small molecular antibacterial agents which are based on the acylated reduced amide scaffold. These molecules display high potency against a panel of Gram-positive and Gram-negative bacteria, including medicinally relevant multidrug-resistant strains. Meanwhile, they also exhibit high potency to inhibit the biofilm formation. Mechanistic studies suggest that these compounds could kill bacteria rapidly, by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). The mechanism is further supported by the fact that the lead compounds do not induce resistance in MRSA bacteria even after 14 passages. Lastly, we also demonstrate that these molecules have therapeutic potential by preventing inflammation caused by MRSA induced pneumonia in a rat model. Compared to HDPs, they merit from facile synthesis and high cost-effectiveness, and therefore they could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.

Small antimicrobial agents based on acylated reduced amide scaffold

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.