Structural insights, immunomodulatory functions, and therapeutic potential of host defense peptides in avoiding antimicrobial resistance.

Antimicrobial resistance (AMR) undermines the effectiveness of antibiotic treatment, and due to this, it now worldwide health concern. In general, antibiotics are used to control or combat bacteria, their widespread and irresponsible has contributed to the development bacterial resistance to some microbial drug. Due to this, treating patients identified with resistant bacteria is burdensome and, expensive, and success rates are low. Among the more successful tools are host defense peptides (HDPs), which represent a beneficial alternative due to their unique mechanisms of action and low toxicity toward host cells. HDPs are crucial innate immune system components, exhibiting antibacterial, antifungal, antiviral, and anti-inflammatory activities. Some peptides, such as human cathelicidin LL-37, exhibit direct pathogen-killing activity and the ability to modulate innate immune responses. HDPs also interact with various pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs), influencing downstream pathways essential for microbial clearance and inflammation regulation. These interactions damage the microbial membrane, stimulating cytokine production and immune cell recruitment. Furthermore, HDPs can modulate chemokine receptor signaling to coordinate leukocyte migration and enhance host protection. Despite these promising aspects, there are challenges to overcome, such as potential immunotoxicity, proteolytic instability, and low receptor specificity, which hinder clinical application. This review highlights the complex interaction between HDPs and immune receptors, which can be used to overcome AMR and inform next-generation anti-infective therapy development.