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Development of New Therapeutics Targeting Biofilm Formation by the Opportunistic Pulmonary Pathogens Pseudomonas Aeruginosa and Aspergillus Fumigatus

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Technical Report,15 Sep 2019,14 Apr 2020

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Hospital for Sick Children Toronto Canada

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Major accomplishments this period 1. BCE5582, a Bacillus cereus orthologue of PelA, previously demonstrated a similar efficiency for biofilm disruption than PelA, a higher resistance to elastase and a longer half-life in mouse lung Major Task 4.Study of that GH variant was therefore continued during this report period. Tolerability and efficacy of BCE5582was comparable to PelA in a neutrophil-depleted model of acute invasive aspergillosis. During the next report period, pharmacokinetics and in vivo efficacy assays will be replicated. 2. In vitro experiments identified the combinations posaconazoleSph3 and caspofunginPelA as the most effective against A. fumigatus Major Task 1. In our neutropenic model of acute aspergillosis, Sph3 potentiated the effect of posaconazole, as measured through the pulmonary fungal burden Major Task 7. The ability of PelA and Sph3 to potentiate caspofungin are now being investigated. During this report period, we determined the optimal dose of caspofungin for potentiation studies in this murine model. During next report period, we will perform the GH caspofungin combination studies in vivo. 3. Ciprofloxacin and ceftazidime in combination with PslGPelA and PslGEga3 exhibited the greatest antibacterial activity in our in vitro assays Major Task 1. In a model of acute murine P. aeruginosa infection, PslGPelA but not PslGEga3 enhanced the activity of ciprofloxacin previous period, Major Task 7. Studies during this report period demonstrated that neither PslGPelA nor PslGEga3 were able to enhance the activity of ceftazidime Major Task 7 in this model of acute infection. In a chronic model of P. aeruginosa pulmonary infection, no potentiation of ciprofloxacin was observed with either PslGPelA or PslGEga3.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Pharmacology

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