Fitness effect of antibiotic resistance in the gut of healthy and immune compromised hosts

Supervisors

Isabel Gordo
GIMM, 1st supervisor

Objectives

Antibiotic resistance (AR) poses a major global health threat, with resistance determinants affecting bacterial fitness differently based on environmental and host factors. This project aims to examine how ciprofloxacin resistance mutations impact bacterial fitness and evolve in vivo within the gut of immune-compromised and control hosts. We hypothesize that the gut’s inflammatory status will alter the fitness dynamics and evolutionary trajectory of AR mutations across these host backgrounds. Specific objectives: • Compare the fitness impact of AR mutations in healthy versus inflamed gut environments in mice with different immune statuses. • Investigate the long-term evolutionary dynamics of ciprofloxacin-resistant strains, identifying compensatory mutations and adaptive changes specific to healthy or diseased gut microbiomes.

Methodology

A key determinant of antibiotic resistance levels is the effect that resistance mutations have on bacteria’ fitness. Several in vitro studies show that resistance typically has a fitness cost in the absence of antibiotics and such cost depends on the environment. Importantly, the fitness cost of antibiotic resistance in vivo, in particular in the context of the gut microbiome, is still poorly understood. The DC will use a classical model of E. coli colonisation of the mouse gut to perform competitive fitness assays between antibiotic resistance and sensitive strains and follow the dynamics of each strain in the intestines of wild-type and IL10KO mice, which are a model of inflammatory bowel disease. IL10KO mice have a distinct gut microbiota composition than wild-type mice and exhibit a higher level of inflammation and of IgA in the gut. Our hypothesis is that the differences in gut environment will affect the fitness effect of antibiotic resistance mutations and their evolutionary dynamics across host genetic backgrounds

Required Skills

Background in microbiology and/or bacteria evolution. Skills in methods of microbiology. Experience in animal experimentation is not mandatory but it is a plus given the goals of this project.

Expected Results

This project will provide insights into the adaptive landscape of antibiotic-resistant bacteria in different gut environments, highlighting how immune status influences AR fitness and evolution. Findings may inform strategies to combat AR persistence by identifying environment-specific compensatory mutations that sustain resistance.

Planned Secondments

BSC (Gabaldón) and Microomics in year 2 (2 months) to train on high-throughput methodologies for microbiome
quantification.
FLI (Valenzano) in year 3 (2 weeks) to learn about microbiome in another model system (killifish).
ICR (Graham) in year 3 (1 week) to get exposed to similar research on drug resistance but applied to cancer.

Enrolment in doctoral programs

PhD Programme of the Lisbon Academic Medical Centre, hosted by the Faculty of Medicine at the University of Lisbon

References

1. L Leonidas Cardoso, P Durao, M Amicone, I Gordo (2020) Dysbiosis individualizes the fitness effect of antibiotic resistance in the mammalian gut. Nature Ecology & Evolution 4 (9), 1268-1278

2. P Durão, R Balbontín, I Gordo (2018) Evolutionary mechanisms shaping the maintenance of antibiotic resistance. Trends in microbiology 26 (8), 677-691

3. HC Barreto, I Gordo (2023) Intrahost evolution of the gut microbiota. Nature Reviews Microbiology 21 (9), 590-603