An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities

Abstract

Antibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections.

Mitigating the Impact of Antibacterial Drug Resistance through Host-Directed Therapies: Current Progress, Outlook, and Challenges

“…treatment with clavanin-MO showed an 80% survival rate. This correlates with a significant decrease (~8 logs) in the number of viable bacterial counts found in the peritoneal fluid of clavanin-MO-treated groups ( 67 ). This illustrates the ability of the antibacterial/immunomodulatory peptide to control inflammation and promote survival of the host following bacterial infection.…”

“…Alternatively, clavanin-MO, a synthetic peptide derived from clavanin A, demonstrated both host immune modulatory functions and direct antimicrobial activity against MDR strains of E. coli and methicillin-resistant S. aureus ( 67 ). In the cell-based study, clavanin-MO modulated immune responses by inducing anti-inflammatory cytokines (e.g., IL-10) and reduced LPS-mediated upregulation of proinflammatory cytokines (e.g., TNF-α and IL-12).…”

Intraperitoneal treatment with antimicrobial peptide rescues mice from a pulmonaryFrancisellainfection

“…Other groups have used peptides to treat a variety of bacterial infections in animal models with varying levels of success. Silva et al treated mice infected with E. coli and S. aureus with peptides derived the marine tunicate Styela clava and found that a single dose of 10 mg/kg yielded survival rates of 80-90% [56]. In another study, it was found that a single 80-200 mg/kg dose boosted survival of rainbow trout infected with Yersinia ruckeri from 20% to 70% [57].…”

Enhancement of Macrophage Function by the Antimicrobial Peptide Sublancin Protects Mice from Methicillin-ResistantStaphylococcus aureus

“…Antimicrobial peptides provide immediately effective, non-specific defenses against infections through direct bactericidal activity or through indirect modulation of the host defense system by enhancing immune-responsive cells (29). Sublancin, produced by Bacillus subtilis 168, has been studied extensively for its antibacterial mechanisms (30, 31).…”