Abstract
Antibiotics are antimicrobial compounds produced by bacteria or fungi that have been used for decades to combat bacterial infections. However, antibiotic resistance has become a global health threat because of the overuse, misuse, and lack of new antibiotic class discovery. The lack of useable antibiotics and the emergence of multidrug-resistant bacteria has thus resulted in an urgent and increasing demand for alternative treatments. Recently, there has been increased interest in host defense peptides (HDPs) and synthetic derivatives, including peptoids, a class of peptidomimetics, to overcome antibiotic-resistant pathogens. Intriguingly, some of these compounds have been identified to exhibit broad-spectrum antimicrobial, antibiofilm, and/or immunomodulatory activity, with a lower risk of causing bacterial resistance. However, natural peptides are therapeutically limited as they are susceptible to proteolytic degradation. Peptoids, on the other hand, are resistant to proteolytic degradation as their structure consists of non-standard amino acids and their side chain is attached to the backbone nitrogen instead of the alpha carbon. As a result, peptoids are more therapeutically advantaged and have been specifically identified as a potential alternative and novel treatment to fight bacterial infections. In this study, we investigated the cytotoxicity of seventeen peptoids on L929 mouse fibroblast cells using a lactate dehydrogenase (LDH) assay and the activity of three lead peptoids, TM1, TM4, and TM5, in a mouse model. From the screen, ten of the seventeen peptoids did not cause cell death up to 100 μg/mL, and the remaining seven caused 50% cell death ranging from 31 μg/mL to 77 μg/mL. Immunomodulatory activity is the modulation of the immune system and can be determined through a change in the production of cytokines, such as TNF⍺ and IL-1β, and chemokines, including CXCL1 and MIP-2. Through an enzyme-linked immunosorbent assay (ELISA), we found that TM1, TM4, and TM5 exhibited immunomodulatory activity. Ultimately, using transcriptome sequencing and analysis of differentially expressed host genes, the host response from the exposure of TM1, TM4, and TM5 was determined. Overall, TM1, TM4, and TM5 exhibited immunomodulatory activity through dysregulating gene expression relating to the immune system and/or wound healing and had notable anti-inflammatory activities. Novel TM peptoids, therefore, have a strong potential to be used as an adjuvant for and/or alternative to antibiotics to combat multidrug-resistant bacterial infections while decreasing the risk of antimicrobial resistance.