UBC Theses and Dissertations
A novel peptide-based treatment for bacterial abscess infections Mansour, Sarah Christine
Methicillin-resistant Staphylococcus aureus (MRSA), a major causative agent of skin infections, is a serious public threat causing a variety of hospital and community-acquired infections. In addition to its high-level mutational resistance, MRSA can form aggregated multicellular communities called biofilms, causing 10- to 1000-fold higher adaptive resistance to conventional antibiotics as compared to free-growing bacteria. Despite biofilm infections representing 65% of all human infections, there is a lack of antibiofilm agents in the drug development pipeline. To combat this issue, I conducted a high-throughput screen on a large peptide library to find peptides with potent anti-MRSA biofilm activity. This led to the identification of a small synthetic cationic peptide composed of D-enantiomeric amino acids, DJK-5, that could inhibit and eradicate pre-formed MRSA biofilms. In a murine cutaneous infection model, DJK-5 drastically reduced the abscess size and dermonecrosis. The peptide also demonstrated broad-spectrum activity in a P. aeruginosa and E. cloacae skin infection murine model. Interestingly, DJK-5 had modest antimicrobial activity and reduced the bacterial loads in abscesses by roughly 10-fold, inferring a mechanism of action distinct from bactericidal activity. Exploring the mechanism of action, it was found that DJK-5 interfered with the production of ppGpp, a conserved stringent response signal employed by bacteria to cope and adapt to environmental stresses. Through transcriptomic analysis, major pathways were shown to be dysregulated by nutritional stress revealing a link between the stringent response, biofilm formation and S. aureus pathogenesis. Importantly, it was demonstrated that the stringent response was critical in mediating lesion formation and that DJK-5 could reduce abscess pathology by interfering with the production of stringent response regulated cutaneous toxins, phenol soluble modulins. DJK-5 revealed a dynamic effect in synergizing with common antibiotics used to treat Gram-positive and Gram-negative infections. These findings provided new insights into the mechanisms governing abscess formation and created a new paradigm for treating multidrug resistant cutaneous abscesses.
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