METAPRO: Metagenomics and genomic approaches for the prevention of the spread of plazomicin resistance in humans, animals and the environment

Antimicrobial resistance is a major Public Health problem. First line antibiotics are starting to be ineffective in many cases against bacterial infections, and the rate at we produce novel antibacterial compounds is not enough to cope with the rate at which the bacteria become resistant. Few antibiotics have been released to the market in the last years, being mostly variations of drugs already in use. In this context, aminoglycosides have risen as a promising solution due to their relative easiness of modification to produce novel effective antibiotics capable of overcome the action of the most prevalent resistance mechanisms. Using this methodology, plazomicin was released to the market in 2018 after being especially engineered to resist the action of most aminoglycoside modifying enzymes, paving the way for the production of novel compounds in this antimicrobial class.

However, the emergence of the acquired 16S rRNA methyltransferases, a resistance mechanism based on the modification of the ribosomal target of the aminoglycosides, endangers the application and development of these next generation aminoglycosides. Since their discovery in 2005, twelve of these enzymes have been identified, conferring high level of resistance to all the clinically relevant aminoglycosides. The prevalence of this resistance mechanism is still considered low, but its common association to resistance genes to first line antibiotics in mobile genetic elements presages a widespread of the acquired 16S rRNA methyltransferases in the upcoming years.

In addition, the study of resistance determinants has been mainly focused on pathogenic bacteria. However, in the last years the spotlight is starting to shift also to non-pathogenic bacteria as a potential source of the antimicrobial resistance genes that we observe in the clinic. The development of the metagenomics approach, where the genomic material of all the microbes present in a certain environment is directly analysed, has boosted the study of resistance determinants in non-pathogenic bacteria, offering a more accurate prevalence levels of these mechanisms, and enabling the prediction of the potential dissemination routes that these genes undergo to end up in pathogenic bacteria.

Therefore, the main objective of the METAPRO PhD project is the application of a metagenomic approach for the study of the resistance determinants to next generation aminoglycosides in ecological niches from human, animal, and environmental origins. We aim to:

1. Evaluate the prevalence of next generation aminoglycosides resistance genes in the different ecological settings.
2. Elucidate the bacterial and ecological reservoirs of these resistance determinants.
3. Predict the potential dissemination routes and describe the clones and mobile genetic elements that entail a major risk of aminoglycoside inefficacy.
4. Analyse the effect of the use of antibiotics in the promotion of selection. of aminoglycoside resistance genes.