Extensive Screening of Genomic and Metagenomic Data Identifies Novel Components of the Macrolide Resistome
Typ
Examensarbete för masterexamen
Program
Biotechnology (MPBIO), MSc
Publicerad
2020
Författare
Lund, David
Modellbyggare
Tidskriftstitel
ISSN
Volymtitel
Utgivare
Sammanfattning
Antibiotic resistance is growing among pathogenic bacteria all across the world,
and has been called one of the most serious threats that humanity is facing. Typically,
bacteria are able to develop resistance as a result of acquiring specific antibiotic
resistance genes from other bacteria though so called horizontal gene transfer.
One commonly used class of antibiotics for which resistance is spreading rapidly is
macrolides. While a lot of research has been devoted to studying the genes that
confer resistance to these antibiotics, the evolution of these macrolide resistance
genes has not been determined. It has been suggested that resistance determinants
that eventually find their way into the clinical environment originate from external
environments, however the mechanisms behind this flow of resistance is not known.
To prevent resistance to macrolide antibiotics from spreading further, it is therefore
important to characterize how the resistance genes have evolved. Furthermore,
knowledge about which genes are present in what environments will help with anticipating
which genes might mobilize into the clinical environment in the future,
and facilitate preemptive measures being taken.
This project aims to use a bioinformatic approach to characterize novel macrolide
resistance genes, applying a computational method called fARGene. To achieve
this, profile hidden Markov models have been developed that are able to identify two
types of genes that confer resistance to macrolides, mediated by enzymes called Erm
23S rRNA methyltransferases and Mph macrolide phosphotransferases respectively,
from biological sequencing data. The models have been used to analyze data representing
over 400,000 bacterial genomes, and over 14 terabases of metagenomic data.
Hundreds of gene families have been identified from the bacterial genomes, most of
which are previously uncharacterized, and these have been analyzed based on their
phylogenetic relationships. The results revealed a large variety of uncharacterized
macrolide resistance genes that seem to have evolved primarily in bacteria from the
phyla Firmicutes and Actinobacteria. In addition, several uncharacterized resistance
genes that have potentially been mobilized have been identified from the results. No
singular origin was determined for either of the analyzed gene classes, however the
previously hypothesized evolutionary relationship between Erm methyltransferases
and the housekeeping methyltransferase KsgA is supported by the results. In addition,
the results from the analysis of metagenomic data indicate that the studied
macrolide resistance genes are likely to mobilize from the human gut, naturally
presenting a way through which the genes may enter the clinical environment.
Beskrivning
Ämne/nyckelord
Antibiotic resistance, Macrolides, Bioinformatics, fARGene, Metagenomics, Evolution