IDR-1

Widespread methicillin-resistant Staphylococcus aureus (S. aureus) infections within community and healthcare settings are responsible for accelerated development of antibiotic resistance. As the antibiotic pipeline began drying up, alternative strategies were sought for future treatment of S. aureus infections. Here, we review immune-based anti-staphylococcal strategies that, unlike conventional antibiotics, target non-essential gene products elaborated by the pathogen. These strategies stimulate narrow or broad host immune mechanisms that are critical for anti-staphylococcal defenses. Alternative approaches aim to disrupt bacterial virulence mechanisms that enhance pathogen survival or induce immunopathology. Although immune-based therapeutics are unlikely to replace antibiotics in patient treatment in the near term, they have the potential to significantly improve upon the performance of antibiotics for treatment of invasive staphylococcal diseases.

Background: The only human cathelicidin, LL-37, and the innate defense regulator peptide IDR-1, which have been proven to have antimicrobial activity, represent essential elements of immunity. Our previous study showed that the peptide LL-37 was protective in vitro to attenuate LTA-induced inflammatory effects. Methicillin-resistant staphylococcus aureus (MRSA) causes a multitude of serious and sometimes life-threatening diseases around the globe. However, the effect of LL-37 and IDR-1 in MRSA-induced pneumonia is unknown. In the present study, we explored the potential of LL-37 and IDR-1 in ameliorating MRSA-induced pneumonia in vivo. Methods: C57BL/6 mice were randomly divided into four groups and perfused intratracheally with PBS, peptide, MRSA and MRSA plus peptide, respectively. Pulmonary tissue pathology, ELISA and quantitative RT-PCR were employed. The relative signal pathways were further explored by western blot analysis. Results: Pathological analysis of the lung tissue sections demonstrated that, when compared with the MRSA-treated group, both the LL-37 and IDR-1 could ameliorate the MRSA-induced pneumonia. The phosphorylation of JNK and Akt were markedly decreased in the peptide plus MRSA-treated group compared with the MRSA-treated group. Furthermore, both of them also reduced TNF-α and IL-6 production in the bronchoalveolar lavage fluid (BALF) and serum in vivo. Conclusion: We report the first evidence of peptides inhibiting inflammation, decreasing the release of inflammatory cytokines and restoring pulmonary function in vivo. The antimicrobial peptide LL-37 and IDR-1 could ameliorate MRSA-induced pneumonia by exerting an anti-inflammatory property and attenuating pro-inflammatory cytokine release, thus providing support for the hypothesis that both innate and synthetic peptides could protect against MRSA in vivo.

Although HDPs were originally hypothesized to act as antimicrobial agents, they also have been shown to broadly modulate the immune response through the activation of different cell types. We recently developed a series of novel, synthetic peptides, termed IDRs, which are conceptually based on a natural HDP, bovine bactenecin. We showed that IDR-1 and IDR-1002 protect the host against bacterial infections through the induction of chemokines. The objective of this study was to investigate the effects of the IDRs on various functions of human neutrophils. Here, we demonstrated that IDR-HH2, IDR-1002, and IDR-1018 modulated the expression of neutrophil adhesion and activation markers. Moreover, these IDRs enhanced neutrophil adhesion to endothelial cells in a β₂ integrin-dependent manner and induced neutrophil migration and chemokine production. The IDR peptides also increased the release of the neutrophil-generated HDPs (antimicrobial), human α-defensins, and LL-37 and augmented neutrophil-mediated killing of Escherichia coli. Notably, the IDRs significantly suppressed LPS-mediated neutrophil degranulation, the release of ROS, and the production of the inflammatory cytokines TNF-α and IL-10, consistent with their ability to dampen inflammation. As evidenced by the inhibitory effects of MAPK-specific inhibitors, IDRs activated the MAPK pathway that was required for chemokine production. In conclusion, our study provides novel evidence regarding the contribution of the IDR peptides to the innate immune response through the modulation of neutrophil functions. The results described here may aid in the development of IDRs as novel, anti-infective and immunomodulatory agents.