Mechanism of action and initial evaluation of a membrane active all-D-enantiomer antimicrobial peptidomimetic

Abstract

Development of therapy against infections caused by antibioticresistant pathogens is a major unmet need in contemporary medicine. In previous work, our group chemically modified an antimicrobial peptidomimetic motif for targeted applications against cancer and obesity. Here, we showthat themodifiedmotif per se is resistant to proteolytic degradation and is a candidate antiinfective agent.We also show that the susceptibility of microorganisms to the drug is independent of bacterial growth phase. Moreover, this peptidomimetic selectively interferes with the integrity and function of the microbial surface lipid bilayer, data indicative that bacterial death results from membrane disruption followed by dissipation of membrane potential. Finally, we demonstrate two potential translational applications: use against biofilms and synergywith antibiotics in use. In summary, we introduce the mechanism of action and the initial evaluation of a prototype drug and a platform for the development of D-enantiomer antimicrobial peptidomimetics that target bacterial membranes of certainGram-negative problempathogenswith promising translational applications.