An anti-infective peptide that selectively modulates the innate immune response

Abstract

We show that an innate defense-regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously.

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers

“…This effect might be related to its tissue distribution and pharmacokinetics, which have not yet been investigated. Alternatively it might have a mechanism similar to some AMPs, which can act indirectly through modulation of the host immune system (45). Thus, the increasing efficacy of 6c with longer delays between doses might be associated with the priming of an immune response, which is then augmented by the second dose.…”

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

“…HDPs are promising new agents [6,14,15,19] that, owing to their unique immunomodulatory mechanisms of action, are less likely to induce bacterial resistance than are conventional antibiotics [14,15]. Moreover, HDPs can also modulate cytokine production to control the inflammatory response [14,15,19,28,38] and thereby may reduce the risk of developing inflammatory osteolysis. IDR-1018 is one of the most attractive of the HDPs [1,26,30,32,37,39,42].…”

“…More recently, evidence has accumulated that the antiinfective effects of HDPs are also the result of their immunomodulatory properties such as upregulation of expression of chemokines that, in turn, recruit and activate host immune cells [6,14,15,19,28,38]. HDPs can also modulate production of pro-and antiinflammatory cytokines to control the inflammatory response [14,15,19,28,38] and can inhibit osteoclast differentiation [20,40] and thereby potentially can reduce inflammatory osteolysis and the lethal consequences of septic shock. As a result of their unique immunomodulatory mechanisms of action, HDPs are also less likely to induce bacterial resistance than are conventional antibiotics [14,15].…”

Immunomodulatory activities of whey β-lactoglobulin tryptic-digested fractions

“…In line with this, it has been shown that several IDRs suppress proinflammatory responses modulating M1eM2 macrophage differentiation (Pena et al, 2013), suppressing potentially harmful excessive inflammatory responses (Scott et al, 2007) and offering protection by enhancing the innate immune defences of the host, thus suggesting again that whey-derived peptides could be used as natural IDRs.…”