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In front of the antibiotic pressure, a wide range of resistance mechanisms exist. They represent an increasing public health issue, which does and will have major consequences on human mortality. Current strategies —mostly based on antibiotic consumption reductions— globally fail to contain this persistent issue. Moreover, even though it is undeniable that the extensive antibiotic use during the past decades has been a driver of antibiotic resistance evolution, its impact on the emergence and the propagation of antibiotic resistance is often overestimated compared to other factors. First, selection on antibiotic resistance cannot be restricted to the medical and veterinary uses of antibiotics. Second, the evolution (i.e. the emergence, maintenance and spread) of a trait in populations also relies on other evolutionary forces and ecological processes. Finally, the intertwining of these factors induces an intricate evolution of resistant phenotypes, relying on several scales ranging from genetic determinism to environmental dynamics. The aim of this thesis is therefore, through an eco-evolutionary approach, to improve the understanding of forces and mechanisms shaping directions and movements of antibiotic resistance genes. To do so, this thesis focuses on aminoglycoside resistance by modifying enzymes. The results of this work highlight the importance of ecological and genomic factors in the circulation of resistance genes, and thus conclude that integrative studies of resistance are thus required. To begin with, this thesis reveals that the distribution of aminoglycoside resistance is loosely linked to variation in aminoglycoside consumption across Europe, but strongly structured by globalization (trade, migration) and even more by ecological connectivity. Subsequent analysis underscores the underestimated role of non-pathogenic bacteria in the horizontal transfer of antibiotic resistance genes at large phylogenetic scales. In the light of these results, this thesis opens up a course of reflection on the study and management of antibiotic resistance., Face à la pression des antibiotiques de nombreux mécanismes de résistances existent. Ces derniers représentent un problème de santé publique qui a et va avoir des conséquences importantes sur la mortalité humaine. Malgré diverses stratégies — principalement basées sur la réduction de la consommation d'antibiotiques — ce problème persistant peine à être contenu. De plus, même s'il est indéniable que l'utilisation massive d'antibiotiques au cours des dernières décennies a été un moteur de l'évolution de la résistance aux antibiotiques, son impact sur l'émergence et la propagation de la résistance aux antibiotiques est souvent surestimé par rapport à d'autres facteurs. Premièrement, la sélection sur la résistance aux antibiotiques ne peut pas être limitée aux antibiotiques à usage humain. Deuxièmement, l'évolution (c'est-à-dire l'émergence, le maintien et la diffusion) d'un trait dans une population repose également sur d'autres forces évolutives et processus écologiques. Enfin, l'entrelacement de ces facteurs résulte en une évolution complexe du phénotype résistant, dépendante de plusieurs échelles allant du déterminisme génétique aux dynamiques environnementales. L'objectif de cette thèse est donc, en s'appuyant sur une approche éco-évolutive, d'améliorer la compréhension des forces et des mécanismes qui façonnent les directions et le mouvement des gènes de résistance aux antibiotiques. Pour ce faire, cette thèse se concentre sur la résistance aux aminoglycosides par le biais d'enzymes d'altération. Les résultats de ces travaux mettent en évidence l'importance des facteurs écologiques et génomiques dans la circulation des gènes de résistance, et concluent ainsi à la nécessité d'études intégratives de la résistance. Dans un premier temps, cette thèse révèle que la distribution de la résistance aux aminoglycosides n'est que très peu liée aux variations de consommation d'aminoglycosides en Europe, mais fortement structurée par la mondialisation (commerce, migration) et plus encore par la connectivité écologique. Une analyse ultérieure souligne le rôle sous-estimé des bactéries non pathogènes dans le transfert horizontal des gènes de résistance aux antibiotiques à grande échelle phylogénétique. A la lumière de ces résultats, cette thèse propose des pistes de réflexion sur l'étude et la gestion des résistances aux antibiotiques.

Additional file 1. Figure S1: Compared running time and memory use for PlasForest and PlasClass.

The durability of host resistance is challenged by the ability of pathogens to escape the defence of their hosts. Understanding the variability in the durability of host resistance is of paramount importance for designing more effective control strategies against infectious diseases. Here, we study the durability of various clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas) alleles of the bacteria Streptococcus thermophilus against lytic phages. We found substantial variability in durability among different resistant bacteria. Since the escape of the phage is driven by a mutation in the phage sequence targeted by CRISPR-Cas, we explored the fitness costs associated with these escape mutations. We found that, on average, escape mutations decrease the fitness of the phage. Yet, the magnitude of this fitness cost does not predict the durability of CRISPR-Cas immunity. We contend that this variability in the durability of resistance may be because of variations in phage mutation rate or in the proportion of lethal mutations across the phage genome. These results have important implications on the coevolutionary dynamics between bacteria and phages and for the optimal deployment of resistance strategies against pathogens and pests. Understanding the durability of CRISPR-Cas immunity may also help develop more effective gene-drive strategies based on CRISPR-Cas9 technology.This article is part of the themed issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

The durability of host resistance is challenged by the ability of pathogens to escape the defence of their hosts. Understanding the variability in the durability of host resistance is of paramount importance for designing more effective control strategies against infectious diseases. Here, we study the durability of various CRISPR (clustered regularly interspaced short palindromic repeats)-Cas alleles of the bacteria Streptococcus thermophilus against lytic phages. We found substantial variability in durability among different resistant bacteria. Since the escape of the phage is driven by a mutation in the phage sequence targeted by CRISPR-Cas, we explored the fitness costs associated with these escape mutations. We found that, on average, escape mutations decrease the fitness of the phage. Yet, the magnitude of this fitness cost does not predict the durability of CRISPR-Cas immunity. We contend that this variability in the durability of resistance may be due to variations in phage mutation rate or in the proportion of lethal mutations across the phage genome. These results have important implications on the coevolutionary dynamics between bacteria and phages and for the optimal deployment of resistance strategies against pathogens and pests. Understanding the durability of CRISPR-Cas immunity may also help develop more effective gene-drive strategies based on CRISPR-Cas9 technology.This article is part of the themed issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.