The extensive utilization of antibiotics has precipitated the emergence of antibiotic-resistant bacteria in recent years. The revelation of Host Defense Peptides （HDPs） has provided a promising avenue for addressing antibiotic-resistant infections. Nevertheless, the practical application of these natural peptides has been impeded by their constrained stability, intricate synthesis process, and elevated cost. Consequently, designing and discovering antimicrobial compounds, including peptide polymers, that mimic HDPs has become a promising solution. A structural design approach has emerged as a classical strategy for developing HDP mimetics. By altering the chemical structure of main chains and side chains, various types of HDP mimetics have been developed, such as α-peptide polymers, β-peptide polymers, polyoxazolines, etc., with high efficacy against antibiotic-resistant bacteria. Furthermore, a mechanism-guided approach is proposed for the design of antimicrobial peptide polymers, taking into account the potential variations in antimicrobial mechanisms associated with chiral and enantiomeric peptides. Helical β-peptide polymers forming α-helical structures upon interaction with bacterial membranes are more effective in disrupting the bacterial membrane, whereas heterochiral β-peptide polymers demonstrate attenuated interactions with cell membranes, thereby facilitating their penetration of bacterial membranes for internal action. This finding has spurred the development of peptide polymers tailored from modifying antimicrobial mechanisms. Additionally, by incorporating biocompatible amino acid residues into the peptide polymers, a class of β-peptide polymers with high efficacy against antibiotic-resistant bacteria and excellent biocompatibility has been identified, offering a promising approach for addressing antibiotic resistance.