Identification of a Small Molecule Inhibitor of the Aminoglycoside 6’-N-Acetyltransferase Type Ib [AAC(6’)-Ib] Using Mixture-Based Combinatorial Libraries
| Autor: | Radleigh G. Santos, Marc A. Giulianotti, Saumya Jani, Kevin Chiem, Veronica Jimenez, Marcelo E. Tolmasky, David L. Lin, Rupali Lad, Ginamarie Debevec, Mary B. Farone, Brock A. Arivett, Clemencia Pinilla, Tung Tran |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Acinetobacter baumannii Pyrrolidines Klebsiella pneumoniae 030106 microbiology Drug Evaluation Preclinical Pyrrolidine Article Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Acetyltransferases medicine Escherichia coli Animals Humans Pharmacology (medical) Amino Acids Enzyme Inhibitors 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Dose-Response Relationship Drug 030306 microbiology Chemistry Aminoglycoside Pentamine General Medicine biochemical phenomena metabolism and nutrition biology.organism_classification 3. Good health Amino acid Anti-Bacterial Agents 030104 developmental biology Infectious Diseases Enzyme HEK293 Cells Biochemistry Amikacin Acetyltransferase medicine.drug |
| DOI: | 10.1101/198176 |
| Popis: | The aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6’)-Ib] is the most widely distributed enzyme among AAC(6’)-I-producing Gram-negative pathogens and confers resistance to clinically relevant aminoglycosides including amikacin. This enzyme is therefore ideal to target with enzymatic inhibitors that could overcome resistance to aminoglycosides. The search for inhibitors was carried out using mixture-based combinatorial libraries, the scaffold ranking approach, and the positional scanning strategy. A library with high inhibitory activity had pyrrolidine pentamine scaffold and was selected for further analysis. This library contained 738,192 compounds with functionalities derived from 26 different amino acids (R1, R2 and R3) and 42 different carboxylic acids (R4) in four R group functionalities. The most active compounds all contained S-phenyl (R1 and R3) and S-hydromethyl (R2) functionalities at three locations and differed at the R4 position. The compound containing 3-phenylbutyl at R4 (compound 206) was a robust enzymatic inhibitor in vitro, in combination with amikacin potentiated the inhibition of growth of three resistant bacteria in culture, and improved survival when used as treatment of Galleria mellonella infected with aac(6’)-Ib-harboring Klebsiella pneumoniae and Acinetobacter baumannii strains. |
| Databáze: | OpenAIRE |
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