Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene
| Autor: | Sven N. Hobbie, Klara Haldimann, Marina Gysin, Katja Becker, Michel Plattner |
|---|---|
| Přispěvatelé: | University of Zurich, Hobbie, Sven N |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Carbapenem Antibiotics 1607 Spectroscopy Paromomycin lcsh:Chemistry Catalytic Domain Databases Genetic Tobramycin lcsh:QH301-705.5 Spectroscopy Genetics Molecular Epidemiology 10179 Institute of Medical Microbiology Aminoglycoside Standard of Care General Medicine Computer Science Applications Anti-Bacterial Agents acetyltransferase Gentamicin 1606 Physical and Theoretical Chemistry medicine.drug medicine.drug_class 1503 Catalysis 030106 microbiology 610 Medicine & health Biology Apramycin Catalysis Article Inorganic Chemistry aac(3)-IV 03 medical and health sciences Structure-Activity Relationship Antibiotic resistance Bacterial Proteins Acetyltransferases Drug Resistance Bacterial Gram-Negative Bacteria medicine 1312 Molecular Biology 1706 Computer Science Applications Humans Nebramycin antimicrobial resistance Physical and Theoretical Chemistry Molecular Biology 1604 Inorganic Chemistry Organic Chemistry Methyltransferases 030104 developmental biology Aminoglycosides lcsh:Biology (General) lcsh:QD1-999 Carbapenems Mutagenesis Site-Directed 570 Life sciences biology Gram-Negative Bacterial Infections Genome Bacterial 1605 Organic Chemistry apramycin |
| Zdroj: | International Journal of Molecular Sciences, Vol 21, Iss 6133, p 6133 (2020) International Journal of Molecular Sciences Volume 21 Issue 17 |
| ISSN: | 1422-0067 |
| Popis: | Aminoglycoside antibiotics are powerful bactericidal therapeutics that are often used in the treatment of critical Gram-negative systemic infections. The emergence and global spread of antibiotic resistance, however, has compromised the clinical utility of aminoglycosides to an extent similar to that found for all other antibiotic-drug classes. Apramycin, a drug candidate currently in clinical development, was suggested as a next-generation aminoglycoside antibiotic with minimal cross-resistance to all other standard-of-care aminoglycosides. Here, we analyzed 591,140 pathogen genomes deposited in the NCBI National Database of Antibiotic Resistant Organisms (NDARO) for annotations of apramycin-resistance genes, and compared them to the genotypic prevalence of carbapenem resistance and 16S-rRNA methyltransferase (RMTase) genes. The 3-N-acetyltransferase gene aac(3)-IV was found to be the only apramycin-resistance gene of clinical relevance, at an average prevalence of 0.7%, which was four-fold lower than that of RMTase genes. In the important subpopulation of carbapenemase-positive isolates, aac(3)-IV was nine-fold less prevalent than RMTase genes. The phenotypic profiling of selected clinical isolates and recombinant strains expressing the aac(3)-IV gene confirmed resistance to not only apramycin, but also gentamicin, tobramycin, and paromomycin. Probing the structure&ndash activity relationship of such substrate promiscuity by site-directed mutagenesis of the aminoglycoside-binding pocket in the acetyltransferase AAC(3)-IV revealed the molecular contacts to His124, Glu185, and Asp187 to be equally critical in binding to apramycin and gentamicin, whereas Asp67 was found to be a discriminating contact. Our findings suggest that aminoglycoside cross-resistance to apramycin in clinical isolates is limited to the substrate promiscuity of a single gene, rendering apramycin best-in-class for the coverage of carbapenem- and aminoglycoside-resistant bacterial infections. |
| Databáze: | OpenAIRE |
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