Mutations in bdcA and valS Correlate with Quinolone Resistance in Wastewater Escherichia coli

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.

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Mutations in bdcA and valS correlate with quinolone resistance in wastewater Escherichia Coli

10.1101/2021.02.12.430739 ◽

2021 ◽

Author(s):

Negin Malekian ◽

Ali Al-Fatlawi ◽

Thomas U. Berendonk ◽

Michael Schroeder

Keyword(s):

Genome Wide Association Study ◽

A Priori ◽

Resistance Mechanisms ◽

Trna Synthetase ◽

Quinolone Resistance ◽

Resistance Mutations ◽

E Coli ◽

Genome Wide ◽

A Genome ◽

Biofilm Dispersal

AbstractSingle 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) correlating over 200,000 mutations against quinolone resistance phenotypes. We uncovered 13 statistically significant mutations including one located at the active site of the biofilm dispersal genes bdcA and six silent mutations in the aminoacyl-tRNA synthetase valS. The study also recovered the known mutations in the topoisomerases gyrA and 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 bdcA and valS may be novel resistance genes with biofilm dispersal and translation as novel resistance mechanisms.

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Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa

Microbiology ◽

10.1099/mic.0.046870-0 ◽

2011 ◽

Vol 157 (4) ◽

pp. 937-944 ◽

Cited By ~ 35

Author(s):

Alex Wong ◽

Rees Kassen

Keyword(s):

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Parallel Evolution ◽

Resistance Mechanisms ◽

Quinolone Resistance ◽

Clinical Samples ◽

Resistance Mutations ◽

Topoisomerase Iv ◽

Therapeutic Implications ◽

Local Differentiation

The emergence and spread of antibiotic resistance in pathogens is a major impediment to the control of microbial disease. Here, we review mechanisms of quinolone resistance in Pseudomonas aeruginosa, an important nosocomial pathogen and a major cause of morbidity in cystic fibrosis (CF) patients. In this quantitative literature review, we find that mutations in DNA gyrase A, the primary target of quinolones in Gram-negative bacteria, are the most common resistance mutations identified in clinical samples of all origins, in keeping with previous observations. However, the identities of non-gyrase resistance mutations vary systematically between samples isolated from CF patients and those isolated from acute infections. CF-derived strains tend to harbour mutations in the efflux pump regulator nfxB, while non-CF strains tend to bear mutations in the efflux regulator mexR or in parC, which encodes one of two subunits of DNA topoisomerase IV. We suggest that differences in resistance mechanisms between CF and non-CF strains result either from local adaptation to different sites of infection or from differences in mutational processes between different environments. We further discuss the therapeutic implications of local differentiation in resistance mechanisms to a common antibiotic.

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