Antimicrobial peptides (AMPs), critical components of the innate immune system, are widely distributed throughout the animal and plant kingdoms. They can protect against a broad array of infection-causing agents, such as bacteria, fungi, parasites, viruses, and tumor cells, and also exhibit immunomodulatory activity. AMPs exert antimicrobial activities primarily through mechanisms involving membrane disruption, so they have a lower likelihood of inducing drug resistance. Extensive studies on the structure-activity relationship have revealed that net charge, hydrophobicity, and amphipathicity are the most important physicochemical and structural determinants endowing AMPs with antimicrobial potency and cell selectivity. This review summarizes the recent advances in AMPs development with respect to characteristics, structure-activity relationships, functions, antimicrobial mechanisms, expression regulation, and applications in food, medicine, and animals. K E Y W O R D S antimicrobial peptides, application, mechanism, structure-activity relationship Med Res Rev. 2019;39:831-859.wileyonlinelibrary.com/journal/med

Poor proteolytic resistance is an urgent problem to be solved in the clinical application of antimicrobial peptides (AMPs), yet common solutions, such as complicated chemical modifications and utilization of d-amino acids, greatly increase the difficulty and cost of producing AMPs. In this work, a set of novel peptides was synthesized based on an antitrypsin/antichymotrypsin hydrolytic peptide structure unit (XYPX) n (X represents I, L, and V; Y represents R and K), which was designed using a systematic natural amino acid arrangement. Of these peptides, 16 with seven repeat units had the highest average selectivity index (GMSI = 99.07) for all of the Gram-negative bacteria tested and remained highly effective in combating Escherichia coli infection in vivo. Importantly, 16 also had dramatic resistance to a high concentration of trypsin/chymotrypsin hydrolysis and exerted bactericidal activity through a membrane-disruptive mechanism. Overall, these findings provide new approaches for the development of antiprotease hydrolytic peptides that target Gram-negative bacteria.

Antimicrobial peptides are an important weapon against invading pathogens and are potential candidates as novel antibacterial agents, but their antifungal activities are not fully developed. In this study, a set of imperfectly amphipathic peptides was developed based on the imperfectly amphipathic palindromic structure R (XRXXXRX)R ( n = 1, 2; X represents L, I, F, or W), and the engineered peptides exhibited high antimicrobial activities against all fungi and bacteria tested (including fluconazole-resistant Candida albicans), with geometric mean (GM) MICs ranging from 2.2 to 6.62 μM. Of such peptides, 13 (I6) (RRIRIIIRIRR-NH) that was Ile rich in its hydrophobic face had the highest antifungal activity (GM = 1.64 μM) while showing low toxicity and high salt and serum tolerance. It also had dramatic LPS-neutralizing propensity and a potent membrane-disruptive mechanism against microbial cells. In summary, these findings were useful for short AMPs design to combat the growing threat of drug-resistant fungal and bacterial infections.

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From the antibacterial fraction of the roots of Garcinia kola, 3؆,4,4ٟ,5,5؆,7,7؆-heptahydroxy-3,8؆-biflavanone (GB1) was isolated as the major constituent, whose interesting conformations were studied on the basis of its 1D and 2D NMR spectra obtained at different temperatures and in different solvents. GB1 showed antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) with MIC of 32 and 128 m mg/ml, respectively.