Peptide IDR‐1018: modulating the immune system and targeting bacterial biofilms to treat antibiotic‐resistant bacterial infections

Abstract

Host defense (antimicrobial) peptides, produced by all complex organisms, typically contain an abundance of positively charged and hydrophobic amino acid residues. A small synthetic peptide termed innate defense regulator (IDR-)1018 was derived by substantial modification of the bovine neutrophil host defense peptide bactenecin. Here, we review its intriguing properties that include anti-infective, anti-inflammatory, wound healing, and anti-biofilm activities. It was initially developed as an immune modulator with an ability to selectively enhance chemokine production and polarize cellular differentiation while suppressing/balancing the pro-inflammatory response. In this regard, it has demonstrated in vivo activity in murine models including enhancement of wound healing and an ability to protect against Staphylococcus aureus, multidrug resistant Mycobacterium tuberculosis, herpes virus, and inflammatory disorders, including cerebral malaria and neuronal damage in a pre-term birth model. More recently, IDR-1018 was shown, in a broad-spectrum fashion, to selectively target bacterial biofilms, which are adaptively resistant to many antibiotics and represent the most common growth state of bacteria in human infections. Furthermore, IDR-1018 demonstrated synergy with conventional antibiotics to both prevent biofilm formation and treat pre-existing biofilms. These data are consistent with a strong potential as an adjunctive therapy against antibiotic-resistant infections.

An Immunomodulatory Peptide Confers Protection in an Experimental Candidemia Murine Model

“…Interestingly, the peptide alone stimulated BMDMs to increase MCP-1 levels comparable to those induced by HKCA treatment. These results are consistent with other studies investigating IDR-1018 in different experimental designs (17,(29)(30)(31). Although our study used a different cell type and inflammatory stimulus, our results indicated that IDR-1018 acts as an anti-inflammatory agent by suppressing proinflammatory cytokines in murine BMDMs challenged with HKCA.…”

“…Innate defense regulator 1018 (IDR-1018) is a 12-amino-acid distantly related peptide variant of bovine HDP Bac2A, designed for improved immunomodulatory activity, besides direct activity, as well as enhancement of antibiotic action against multidrugresistant bacteria and a broad spectrum of bacterial biofilms, protection against cerebral malaria, and preservation of osseointegration (14)(15)(16)(17). However, to date, the activity of this peptide against human-pathogenic fungi had not been described.…”

Synthetic antibiofilm peptides

“…Peptide 1018 was subsequently shown to induce killing of bacteria present within oral multispecies biofilms [35], therefore identifying a promising role of this agent for plaque disinfection in dentistry. It is worth mentioning that, like LL-37, peptide 1018 (also termed IDR-1018) is a potent modulator of innate immunity and as such is able to suppress inflammation and enhance protective immunity in several animal infection models [36]. …”

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

“…Innate defense regulator peptide-1018 (IDR-1018) is a synthetic 12-amino acid derivative of bactenecin, a bovine HDP [42]. IDR-1018 can directly kill bacteria [42], can modulate differentiation and activation of macrophages and neutrophils, thereby regulating their production of chemokines and cytokines [1,26,30,32,37,42], can reduce soft tissue infections [1,37], and can disrupt bacterial biofilms [25,35]. IDR-1018 was chosen as the focus of this study because it is the most potent IDR that has been described [37] and is therefore an attractive agent to potentially reduce orthopaedic infections and inflammatory osteolysis around orthopaedic implants.…”