A novel approach for emerging and antibiotic resistant infections: Innate defense regulators as an agnostic therapy

J Biotechnol. 2016 May 20;226:24-34. doi: 10.1016/j.jbiotec.2016.03.032. Epub 2016 Mar 23.

Abstract

Innate Defense Regulators (IDRs) are short synthetic peptides that target the host innate immune system via an intracellular adaptor protein which functions at key signaling nodes. In this work, further details of the mechanism of action of IDRs have been discovered. The studies reported here show that the lead clinical IDR, SGX94, has broad-spectrum activity against Gram-negative and Gram-positive bacterial infections caused by intracellular or extracellular bacteria and also complements the actions of standard of care antibiotics. Based on in vivo and primary cell culture studies, this activity is shown to result from the primary action of SGX94 on tissue-resident cells and subsequent secondary signaling to activate myeloid-derived cells, resulting in enhanced bacterial clearance and increased survival. Data from non-clinical and clinical studies also show that SGX94 treatment modulates pro-inflammatory and anti-inflammatory cytokine levels, thereby mitigating the deleterious inflammatory consequences of innate immune activation. Since they act through host pathways to provide both broad-spectrum anti-infective capability as well as control of inflammation, IDRs are unlikely to be impacted by resistance mechanisms and offer potential clinical advantages in the fight against emerging and antibiotic resistant bacterial infections.

Keywords: Anti-infective; Anti-inflammatory; Antibacterial; Broad spectrum; Cefepime (PubChem CID: 9571075); Doxycycline (PubChem CID: 54671203); Dusquetide (PubChem CID: 71722017); Immune; Innate; Vancomycin (PubChem CID: 14969).

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Cell Movement / drug effects
  • Cytokines / metabolism
  • Drug Resistance, Microbial* / drug effects
  • Female
  • Half-Life
  • Humans
  • Immunity, Innate*
  • Macaca fascicularis
  • Male
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Mice, Inbred BALB C
  • Middle Aged
  • Peritoneum / drug effects
  • Peritoneum / pathology
  • Rats, Sprague-Dawley
  • Spleen / pathology
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents
  • Cytokines