Design and synthesis of broad-spectrum antimicrobial amphiphilic peptidomimetics to combat drug-resistance

Abstract

The gradual depletion of antibiotic discovery pipeline makes the antibiotic resistance a difficult clinical problem and a global health emergency. The membrane-active antimicrobial peptides (AMPs) attracted much attention due to a lower tendency to bacterial resistance than traditional antibiotics. However, some immanent drawbacks of AMPs may hamper their application in combating antibiotic resistance in the long run, such as susceptible to enzymatic degradation and low cell permeability. Herein, we report the design and synthesis of a novel series of amphiphilic peptidomimetics, from which we identified compounds that exhibited potent antimicrobial activity against a panel of clinically relevant Gram-positive and Gram-negative bacteria strains. The most potent compound 20 (SD-110-12) is able to kill intracellular bacterial pathogens and prevent the development of bacterial resistance under the tested conditions by targeting cell membranes. Additionally, compound 20 (SD-110-12) obtains good in vivo efficacy that is comparative to vancomycin by eradicating MRSA and suppressing inflammation in a mice infected skin wound model, demonstrating its promising therapeutic potential.