Biology subjects

L'Heureux, J.

Publications and source records attributed to L'Heureux, J..

3 recordsLinked to original sources

bioRxiv2022

Synthetic extremophiles: Species-specific formulations for microbial therapeutics and beyond.

Microorganisms have been used for millennia to produce food and medicine and are now being developed as products themselves to treat disease and boost crop production. However, as required for these new applications, maintaining high viability throughout manufacturing, transportation and use remains a significant challenge requiring sophisticated cold-chains and packaging. In fact, we found that commercial microbial products (probiotics) provide a poor solution to this challenge, in particular for key industrial organisms like E. coli. To overcome this technological gap, we report the development of synthetic extremophiles of industrially important gram-negative bacteria (E. coli Nissle 1917, Ensifer meliloti), gram positive bacteria (Lactobacillus plantarum) and yeast (Saccharomyces boulardii). Specifically, we developed a high throughput pipeline to define species-specific materials that allow these organisms to survive drying, elevated temperatures, organic solvents and even ionizing radiation. We enhanced the stability of E.coli Nissle 1917 by >4 orders of magnitude over commercial formulations and demonstrate the capacity to remain viable while undergoing tableting and pharmaceutical methodologies involving organic solvents. The development of synthetic materials-based enhanced stabilization stands to transform our capacity to apply micro-organisms in extreme environments including those found on Earth as well as in space. One-Sentence SummaryFragile therapeutic bacteria can be made to survive the manufacturing extremes normally reserved for small molecule drugs.

microbiology↗

bioRxiv2019

Computationally guided high-throughput design of self-assembling drug nanoparticles

Nanoformulations are transforming our capacity to effectively deliver and treat a myriad of conditions. However, many nanoformulation approaches still suffer from high production complexity and low drug loading. One potential solution relies on harnessing co-assembly of drugs and small molecular excipients to facilitate nanoparticle formation through solvent exchange without the need for chemical synthesis, generating nanoparticles with up to 95% drug loading. However, there is currently no understanding which of the millions of possible combinations of small molecules can result in the formation of these nanoparticles. Here we report the development of a high-throughput screening platform coupled to machine learning to enable the rapid evaluation of such nanoformulations. Our platform identified 101 novel self-assembling drug nanoparticles from 2.1 million pairings derived from 788 candidate drugs with one of 2686 excipients, spanning treatments for multiple diseases and often harnessing well-known food additives, vitamins, or approved drugs as carrier materials - with potential for accelerated approval and translation. Given their long-term stability and potential for clinical impact, we further characterize novel sorafenib-glycyrrhizin and terbinafine-taurocholic acid nanoparticles ex vivo and in vivo. We anticipate that this platform could accelerate the development of safer and more efficacious nanoformulations with high drug loadings for a wide range of therapeutics.

bioengineering↗

bioRxiv2016

Genome-Wide Fitness Analyses of the Foodborne Pathogen Campylobacter jejuni in In Vitro and In Vivo Models

Infection by Campylobacter is recognised as the most common cause of foodborne bacterial illness worldwide. Faecal contamination of meat, especially chicken, during processing represents a key route of transmission to humans. There is currently no licenced vaccine and no Campylobacter-resistant chickens. In addition, preventative measures aimed at reducing environmental contamination and exposure of chickens to Campylobacter jejuni (biosecurity) have been ineffective. There is much interest in the factors/mechanisms that drive C. jejuni colonisation and infection of animals, and survival in the environment. It is anticipated that understanding these mechanisms will guide the development of effective intervention strategies to reduce the burden of C. jejuni infection. Here we present a comprehensive analysis of C. jejuni fitness during growth and survival within and outside hosts. A comparative analysis of transposon (Tn) gene inactivation libraries in three C. jejuni strains by Tn-seq demonstrated that a large proportion, 331 genes, of the C. jejuni genome is dedicated to (in vitro) growth. An extensive Tn library in C. jejuni M1cam (~10,000 mutants) was screened for the colonisation of commercial broiler chickens, survival in houseflies and under nutrient-rich and-poor conditions at low temperature, and infection of human gut epithelial cells. We report C. jejuni factors essential throughout its life cycle and we have identified genes that fulfil important roles across multiple conditions, including maf3, fliW, fliD, pflB and capM, as well as novel genes uniquely implicated in survival outside hosts. Taking a comprehensive screening approach has confirmed previous studies, that the flagella are central to the ability of C. jejuni to interact with its hosts. Future efforts should focus on how to exploit this knowledge to effectively control infections caused by C. jejuni.\n\nAuthor SummaryCampylobacter jejuni is the leading bacterial cause of human diarrhoeal disease. C. jejuni encounters and has to overcome a wide range of \"stress\" conditions whilst passing through the gastrointestinal tract of humans and other animals, during processing of food products, on/in food and in the environment. We have taken a comprehensive approach to understand the basis of C. jejuni growth and within/outside host survival, with the aim to inform future development of intervention strategies. Using a genome-wide transposon gene inactivation approach we identified genes core to the growth of C. jejuni. We also determined genes that were required during the colonisation of chickens, survival in the housefly and under nutrient-rich and -poor conditions at low temperature, and during interaction with human gut epithelial tissue culture cells. This study provides a comprehensive dataset linking C. jejuni genes to growth and survival in models relevant to its life cycle. Genes important across multiple models were identified as well as genes only required under specific conditions. We identified that a large proportion of the C. jejuni genome is dedicated to growth and that the flagella fulfil a prominent role in the interaction with hosts. Our data will aid development of effective control strategies.

microbiology↗