Abstract
Single mutations can confer resistance to antibiotics. Identifying such mutations can help to develop and improve drugs. Here, we systematically screen for candidate quinolone resistance-conferring mutations. We sequenced highly diverse wastewater E. coli and performed a genome-wide association study (GWAS) to determine associations between over 200,000 mutations and quinolone resistance phenotypes. We uncovered 13 statistically significant mutations including 1 located at the active site of the biofilm dispersal gene bdcA and 6 silent mutations in the aminoacyl-tRNA synthetase valS. The study also recovered the known mutations in the topoisomerases gyrase (gyrA) and topoisomerase IV (parC). In summary, we demonstrate that GWAS effectively and comprehensively identifies resistance mutations without a priori knowledge of targets and mode of action. The results suggest that mutations in the bdcA and valS genes, which are involved in biofilm dispersal and translation, may lead to novel resistance mechanisms.
Highlights
Sci. 2021, 22, 6063. https://doi.org/In the 1960s, an impurity during the synthesis of the antimalarial chloroquine led to the discovery of nalidixic acid [1,2]
We aimed to identify mutations that correlate with quinolone resistance
After extracting raw variants from 99 wastewater E. coli genomes, we reduced raw to high-quality variants
Summary
In the 1960s, an impurity during the synthesis of the antimalarial chloroquine led to the discovery of nalidixic acid [1,2]. Two years after its introduction to the market, resistances were observed, but it took even more years before the drug’s targets and mechanism of action were understood [1,3]. In 1964 and 1990, gyrase (gyrA) and topoisomerase IV (parC) were discovered as the drug’s primary and secondary targets, respectively [1]. Improved derivatives of nalidixic acid were found, such as norfloxacin, ciprofloxacin, and levofloxacin. There are over 20 fluoroquinolones on the market. Fluoroquinolones act by converting their targets, gyrase (gyrA) and topoisomerase IV (parC), into toxic enzymes that fragment the bacterial chromosome [4]
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