Increased power from conditional bacterial genome-wide association identifies macrolide resistance mutations in Neisseria gonorrhoeae
| Autor: | Leonor Sánchez-Busó, Tatum D. Mortimer, Kevin C. Ma, Marissa A. Duckett, Allison L. Hicks, Nicole E. Wheeler, Yonatan H. Grad |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Science 030106 microbiology General Physics and Astronomy Genome-wide association study Drug resistance Microbial Sensitivity Tests Biology Azithromycin medicine.disease_cause Antimicrobial resistance General Biochemistry Genetics and Molecular Biology Article Bacterial genetics 03 medical and health sciences Gonorrhea Drug Resistance Bacterial medicine Humans lcsh:Science Bacterial genomics Genetic association Genetic association study Genetics Mutation Multidisciplinary Binding Sites General Chemistry Macrolide binding Neisseria gonorrhoeae Anti-Bacterial Agents RNA Ribosomal 23S 030104 developmental biology lcsh:Q Macrolides Pathogens Genome Bacterial medicine.drug Genome-Wide Association Study |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-8 (2020) |
| ISSN: | 2041-1723 |
| Popis: | The emergence of resistance to azithromycin complicates treatment of Neisseria gonorrhoeae, the etiologic agent of gonorrhea. Substantial azithromycin resistance remains unexplained after accounting for known resistance mutations. Bacterial genome-wide association studies (GWAS) can identify novel resistance genes but must control for genetic confounders while maintaining power. Here, we show that compared to single-locus GWAS, conducting GWAS conditioned on known resistance mutations reduces the number of false positives and identifies a G70D mutation in the RplD 50S ribosomal protein L4 as significantly associated with increased azithromycin resistance (p-value = 1.08 × 10−11). We experimentally confirm our GWAS results and demonstrate that RplD G70D and other macrolide binding site mutations are prevalent (present in 5.42% of 4850 isolates) and widespread (identified in 21/65 countries across two decades). Overall, our findings demonstrate the utility of conditional associations for improving the performance of microbial GWAS and advance our understanding of the genetic basis of macrolide resistance. The mechanisms underlying resistance of Neisseria gonorrhoeae to the antibiotic azithromycin are incompletely understood. Here, Ma et al. conduct a conditional genome-wide association study to identify new resistance mutations and experimentally confirm that a mutation in ribosomal protein L4 confers increased resistance. |
| Databáze: | OpenAIRE |
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