Biological Cost of Single and Multiple Norfloxacin Resistance Mutations in Escherichia coli Implicated in Urinary Tract Infections
| Autor: | Niels Frimodt-Møller, Diarmaid Hughes, Dorthe Sandvang, Patricia Komp Lindgren, Linda L. Marcusson |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Mutant
Microbial Sensitivity Tests Biology medicine.disease_cause DNA gyrase Microbiology Evolution Molecular Mice Anti-Infective Agents Mechanisms of Resistance Drug Resistance Bacterial medicine Escherichia coli Animals Humans Pharmacology (medical) Norfloxacin Escherichia coli Infections Antibacterial agent Pharmacology Mutation Escherichia coli Proteins biochemical phenomena metabolism and nutrition biology.organism_classification bacterial infections and mycoses Enterobacteriaceae Infectious Diseases Urinary Tract Infections bacteria Efflux medicine.drug |
| Popis: | Resistance to fluoroquinolones in urinary tract infection (UTIs) caused by Escherichia coli is associated with multiple mutations, typically those that alter DNA gyrase and DNA topoisomerase IV and those that regulate AcrAB-TolC-mediated efflux. We asked whether a fitness cost is associated with the accumulation of these multiple mutations. Mutants of the susceptible E. coli UTI isolate Nu14 were selected through three to five successive steps with norfloxacin. Each selection was performed with the MIC of the selected strain. After each selection the MIC was measured; and the regions of gyrA , gyrB , parC , and parE , previously associated with resistance mutations, and all of marOR and acrR were sequenced. The first selection step yielded mutations in gyrA , gyrB , and marOR . Subsequent selection steps yielded mutations in gyrA , parE , and marOR but not in gyrB , parC , or acrR . Resistance-associated mutations were identified in almost all isolates after selection steps 1 and 2 but in less than 50% of isolates after subsequent selection steps. Selected strains were competed in vitro, in urine, and in a mouse UTI infection model against the starting strain, Nu14. First-step mutations were not associated with significant fitness costs. However, the accumulation of three or more resistance-associated mutations was usually associated with a large reduction in biological fitness, both in vitro and in vivo. Interestingly, in some lineages a partial restoration of fitness was associated with the accumulation of additional mutations in late selection steps. We suggest that the relative biological costs of multiple mutations may influence the evolution of E. coli strains that develop resistance to fluoroquinolones. |
| Databáze: | OpenAIRE |
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