Antimicrobial host defence peptides: functions and clinical potential

Abstract

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally-occurring peptides which can combat infections through their direct microbicidal properties and/or by influencing the host's immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been employed to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies. This has led to the adoption of the current name for this family of peptides, Cationic Host Defence Peptides, which encompasses the wide range of described functions. Over the last three decades there has been substantial interest in therapeutically harnessing CHDP, with more than 5000 papers published in this area of research since 2017 alone. These include the examination of potential clinical uses for CHDP ranging from infections including multidrug-resistant bacteria 16-19 , to chronic inflammatory diseases such as arthritis 20 , asthma 21 and colitis 22 , as well as some cancers 23. Peptide-based therapeutics currently in clinical trials are primarily for the treatment of infections such as respiratory, oral and catheter-related infections, and for wound healing (see http://dramp.cpu-bioinfor.org/browse/ClinicalTrialsData.php). This review will provide an overview of current understanding of the scope of functions of CHDP, primarily from eukaryotes. Emerging therapeutic applications of these peptides, current clinical trials and the associated clinical developmental challenges will be discussed. Although there is increasing interest in the development of non-peptide mimics of CHDP for therapeutic application, such as peptoid analogs (reviewed in 24), a comprehensive discussion of these approaches is beyond the scope of this review. [H1] Naturally occurring CHDP The antimicrobial peptide database has catalogued more than 2600 natural antimicrobial peptides, including those annotated as immunomodulatory 25. The major families of CHDP from eukaryotes that are of interest from a drug discovery perspective are summarized below. [H2] Vertebrate CHDP CHDP from vertebrates have an essential role in the first line of defense against microbial pathogens. Upon infection, CHDP can kill pathogens through diverse mechanisms 26-31 (discussed below), acting rapidly and directly on the pathogen when present in high local concentrations, or indirectly to modify components of host defense. These peptides exhibit immunomodulatory activities that can be either pro-or anti-inflammatory depending on the phase of the infection (see below) 12-14,29. CHDP from vertebrates are amphipathic peptides containing amino acids with hydrophilic and hydrophobic side chains at opposite sides of the molec...

Inoculum effect of antimicrobial peptides

“…While the IE is well-characterized for traditional antibiotics, little is known about this phenomenon for other antimicrobial compounds. Antimicrobial peptides (AMPs), sometimes referred to as "host-defense peptides", are produced by all living organisms as a first line of defense against pathogens [Zasloff 2002, Mookherjee 2020, Lazzaro 2020. These peptides can have many functions [Hancock 2016], but most of them cause direct bactericidal effects that typically involve perturbation of the membrane integrity of microbial cells [Lazzaro 2020.…”

“…When a threshold of membrane-bound molecules is reached, the stress is released by the formation of pores or other membrane defects. This mechanism of action has been termed the "carpet" model [Gazit 1996, and it makes development of bacterial resistance particularly difficult [Wimley 2010, Fox 2013, Mookherjee 2020.…”

Human Defensins: A Novel Approach in the Fight against Skin Colonizing Staphylococcus aureus

“…AMPs also appear to have a pathogenic function in AD, as they favor the production of Th2-derived cytokines implicated in the pathogenesis of AD [98]. In addition, it has been hypothesized that HBD3 has a skin barrier function, which is damaged in AD [99].…”

Antimicrobial peptide induced-stress rendersStaphylococcus aureussusceptible to toxic nucleoside analogues

“…Reasons that make AMPs attractive are their high diversity across the tree of life (Wang and Wang, 2004) and the finding that albeit drug resistance evolves against AMPs (Perron et al, 2006;Habets and Brockhurst, 2012; Lofton et al, 2013;Johnston et al, 2016;Makarova et al, 2018), it evolves at a much lower probability in comparison to conventional antibiotics (Yu et al, 2018;Spohn et al, 2019). One common problem with the development of AMPs as drugs is that, under physiological conditions, their antimicrobial activity cannot easily recaptured and the required dosage is extremely high (Mookherjee et al, 2020). This dosage issue can be addressed by making use of synergistic combinations of AMPs (Yu et al, 2016), a property common in natural defense cocktails (Westerhoff et al, 1989;Yan and Hancock, 2001).…”