Antibiotic resistance is one of the biggest public concerns in the 21st century. Host-defense
peptides (HDPs) can potentially mitigate the problem through bacterial membrane disruption; however,
they suffer from moderate activity and low stability. We recently developed a new class of peptidomimetics
termed “AApeptides”. This class of peptidomimetics can mimic the mechanism of action
of HDPs, and effectively arrest the growth of multidrug resistant Gram-positive and Gram-negative
bacteria. As they are built on unnatural backbone, they are resistant to proteolytic degradation. In this
review, we summarize the development of this class of antimicrobial peptidomimetics, and discuss the
future perspective on how they can move forward on combating antibiotic resistance.