Exploration into the origins and mobilization of di-hydrofolate reductase genes and the emergence of clinical resistance to trimethoprim
Sánchez-Osuna, Miquel (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Cortés Garmendia, M. Pilar (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Llagostera Casas, Montserrat (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Barbé García, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Erill, Ivan (University of Maryland. Department of Biological Sciences)

Data:	2020
Resum:	Trimethoprim is a synthetic antibacterial agent that targets folate biosynthesis by competitively binding to the di-hydrofolate reductase enzyme (DHFR). Trimethoprim is often administered synergistically with sulfonamide, another chemotherapeutic agent targeting the di-hydropteroate synthase (DHPS) enzyme in the same pathway. Clinical resistance to both drugs is widespread and mediated by enzyme variants capable of performing their biological function without binding to these drugs. These mutant enzymes were assumed to have arisen after the discovery of these synthetic drugs, but recent work has shown that genes conferring resistance to sulfonamide were present in the bacterial pangenome millions of years ago. Here, we apply phylogenetics and comparative genomics methods to study the largest family of mobile trimethoprim-resistance genes (dfrA). We show that most of the dfrA genes identified to date map to two large clades that likely arose from independent mobilization events. In contrast to sulfonamide resistance (sul) genes, we find evidence of recurrent mobilization in dfrA genes. Phylogenetic evidence allows us to identify novel dfrA genes in the emerging pathogen , and we confirm their resistance phenotype in vitro. We also identify a cluster of dfrA homologues in cryptic plasmid and phage genomes, but we show that these enzymes do not confer resistance to trimethoprim. Our methods also allow us to pinpoint the chromosomal origin of previously reported dfrA genes, and we show that many of these ancient chromosomal genes also confer resistance to trimethoprim. Our work reveals that trimethoprim resistance predated the clinical use of this chemotherapeutic agent, but that novel mutations have likely also arisen and become mobilized following its widespread use within and outside the clinic. Hence, this work confirms that resistance to novel drugs may already be present in the bacterial pangenome, and stresses the importance of rapid mobilization as a fundamental element in the emergence and global spread of resistance determinants.
Ajuts:	Ministerio de Economía y Competitividad BIO2016-77011-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Trimethoprim ; Antibiotics ; Chemotherapeutic agent ; Resistance ; Sulfonamides ; Phylogenetics ; Evolution
Publicat a:	Microbial Genomics, Vol. 6, Issue 11 (September 2020) , art. 440, ISSN 2057-5858

DOI: 10.1099/mgen.0.000440
PMID: 32969787

13 p, 4.6 MB

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