Drug Delivery Systems for the Oral Administration of Antimicrobial Peptides: Promising Tools to Treat Infectious Diseases

Abstract

Antimicrobial peptides (AMPs) have a great potential to face the global expansion of antimicrobial resistance (AMR) associated to the development of multidrug-resistant (MDR) pathogens. AMPs are usually composed of 10-50 amino acids with a broad structural diversity and present a range of antimicrobial activities. Unfortunately, even if the oral route is the most convenient one, currently approved therapeutic AMPs are mostly administrated by the intravenous route. Thus, the development of novel drug delivery systems (DDSs) represents a promising opportunity to protect AMPs from chemical and enzymatic degradation through the gastrointestinal tract and to increase intestinal permeability leading to high bioavailability. In this review, the classification and properties as well as mechanisms of the AMPs used in infectiology are first described. Then, the different pharmaceutical forms existing in the market for oral administration are presented. Finally, the formulation technologies, including microparticle- and nanoparticle-based DDSs, used to improve the oral bioavailability of AMPs are reviewed.

Keywords: antimicrobial peptides (AMPs); drug delivery systems (DDS); infectiology; oral route; pharmaceutical forms.

Figure 1

Structural diversity of antimicrobial peptides (AMPs) and their activities against bacteria, viruses, or fungi. A wide variety of biological sources, including microbes, insects, amphibians, reptiles, mammals, or plants, produce AMPs, which are classified into five structural classes. Representative examples of these five classes are shown as a cartoon representation and colored by hydrophobicity [sourced from the RCSB Protein Data Bank (https://www.rcsb.org/)]: (A) α-helical structure of human LL-37 (PDB entry: 2K6O); (B) β-sheet structure of bovine lactoferricin (PDB entry: 1LFC); (C) α-helix and β-sheet structure of human beta-defensin-1 (PDB entry: 1IJV); (D) Linear extension structure of bovine indolicidin (PDB entry: 1G89); (E) Cyclic structure of Bacillus subtilis Subtilisin A (PDB entry: 1PXQ). Direct pathogen killing and immunomodulatory activities of AMPs lead to antibacterial, antiviral, and antifungal activities. AMPs' advantages and limitations to treat infectious diseases are listed.

Figure 2

Barriers of AMP absorption and interest of drug delivery systems by oral route. Current drug delivery systems (DDS), including microparticles, nanoparticles, liposomes, and self-emulsifying drug delivery systems (SEDDS), are assessed for oral antimicrobial peptides (AMPs) administration. The encapsulation of AMPs in DDS presents advantages to avoid gastrointestinal barriers.