Investigating Potential Therapeutic Activity of Designed Histone Derived Antimicrobial Peptides through Hybridization and Antibiotic Cocktails

Abstract

Modern medicine is contingent on innovation in order to best face the myriad of challenges to human health and the evolution of organisms such as bacteria. Due to increasing antibiotic resistance to small molecule antibiotics in bacteria, there is a need for alternative therapeutic routes and options. One potential alternative is antimicrobial peptides (AMPs), which have a broad range of antimicrobial activity and are found as part of the innate immune response of many organisms. Through research and exploration of these AMPs we look to improve their antimicrobial activity. Our current research investigates these two approaches utilizing novel histone derived antimicrobial peptides (HDAPs). These peptides are based on buforin II (BF2), DesHDAP1, and DesHDAP2. In one approach we hybridize two peptides into a single, longer AMP. In the other approach we combine AMPs with conventional antibiotics. Studies have shown that some hybrid peptides are more effective against bacteria and less toxic to mammalian cells than the lone parent peptides. Similarly, using two therapeutics can yield synergistic effects, proving more beneficial combined than alone. Thus far, the hybrid peptides demonstrate increased antibacterial activity compared to the individual parent peptides, and some show much greater activity depending on the order of the parent peptides and the amino acid linker utilized. DesHDAP2 has antimicrobial activity when used alone comparable to that of BF2. Trials running DesHDAP2 in combination with several conventional antibiotics with differing mechanisms of action have noted potentially synergistic combinations. Ongoing work will determine if there are any harmful side effects to eukaryotic cells from these two therapeutic approaches.