Chan, H. K. | bioRxiv Science

bioRxiv2020

Pharmacokinetics and pharmacodynamics of inhaled antipseudomonal bacteriophage therapy in mice

Inhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different to antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate the in vivo PK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in mice. BALB/c mice were administered phage PEV31 at doses of 107 and 109 PFU by the intratracheal route. Mice (n = 4) were sacrificed at 0, 1, 2, 4, 8 and 24 h post-treatment and various tissues (lungs, kidney, spleen and liver), bronchoalveolar lavage and blood were collected for phage quantification. In a separate study, mice (n = 4) were treated with PEV31 (109 PFU) or PBS at 2 h post-inoculation with MDR P. aeruginosa. Infective PEV31 and bacteria were enumerated from the lungs. In the phage only study, PEV31 titer gradually decreased in the lungs over 24 hours with a half-life of approximately 8 h for both doses. In the presence of bacteria, PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Some phage-resistant colonies were observed from the lung homogenates sampled at 24 h post-phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.

pharmacology and toxicology↗

bioRxiv2017

Mixtures are more salient stimuli in olfaction

In their natural environment, animals often encounter complex mixtures of odours. It is an open question whether and how responses to complex mixtures of multi-component odours differ from those to simpler mixtures or single components. To approach this question, we built a full-size model of the early olfactory system of honeybees, which predicts responses to both single odorants and mixtures. The model is designed so that olfactory response patterns conform to the statistics derived from experimental data for a variety of their properties. It also takes into account several biophysical processes at a minimal level, including processes of chemical binding and activation in receptors, and spike generation and transmission in the antennal lobe network. We verify that key findings from other experimental data, not used in building the model, are reproduced in it. In particular, we replicate the strong correlation among receptor neurons and the weaker correlation among projection neurons observed in experimental data and show that this decorrelation is predominantly due to inhibition by interneurons. By simulation and mathematical analysis of our model, we demonstrate that the chemical processes of receptor binding and activation already lead to significant differences between the responses to mixtures and those to single component stimuli. On average, the response latency of olfactory receptor neurons at low stimulus concentrations is reduced and the response patterns become less variable across concentrations as the number of odour components in the stimulus increases. These effects are preserved in the projection neurons. Our results suggest that the early olfactory system of insects may be particularly efficient in processing mixtures, which corresponds well to the observation that chemical signalling in nature predominantly involves mixtures.

neuroscience↗