Designed Small-Molecule Inhibitors of the Anthranilyl-CoA Synthetase PqsA Block Quinolone Biosynthesis in Pseudomonas aeruginosa
| Autor: | Debarshi Pratihar, Damien Maura, Cheng Ji, Indrajeet Sharma, J P Coleman, L. Lynn Hudson, Derek S. Tan, Tezcan Guney, Laurence G. Rahme, Everett C. Pesci |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.drug_class Virulence Quinolones Biology medicine.disease_cause 01 natural sciences Biochemistry Microbiology Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Biosynthesis Coenzyme A Ligases medicine Enzyme Inhibitors Pathogen Transcription factor 030304 developmental biology 0303 health sciences 010405 organic chemistry Pseudomonas aeruginosa General Medicine Articles Quinolone Small molecule 0104 chemical sciences Quorum sensing 030104 developmental biology chemistry 030220 oncology & carcinogenesis Molecular Medicine |
| Zdroj: | ACS Chemical Biology |
| ISSN: | 1554-8937 |
| Popis: | The Gram-negative bacterial pathogen Pseudomonas aeruginosa uses three interconnected intercellular signaling systems regulated by the transcription factors LasR, RhlR, and MvfR (PqsR), which mediate bacterial cell-cell communication via small-molecule natural products and control the production of a variety of virulence factors. The MvfR system is activated by and controls the biosynthesis of the quinolone quorum sensing factors HHQ and PQS. A key step in the biosynthesis of these quinolones is catalyzed by the anthranilyl-CoA synthetase PqsA. To develop inhibitors of PqsA as novel potential antivirulence antibiotics, we report herein the design and synthesis of sulfonyladeonsine-based mimics of the anthranilyl-AMP reaction intermediate that is bound tightly by PqsA. Biochemical, microbiological, and pharmacological studies identified two potent PqsA inhibitors, anthranilyl-AMS (1) and anthranilyl-AMSN (2), that decreased HHQ and PQS production in P. aeruginosa strain PA14. However, these compounds did not inhibit production of the virulence factor pyocyanin. Moreover, they exhibited limited bacterial penetration in compound accumulation studies. This work provides the most potent PqsA inhibitors reported to date and sets the stage for future efforts to develop analogues with improved cellular activity to investigate further the complex relationships between quinolone biosynthesis and virulence factor production in P. aeruginosa and the therapeutic potential of targeting PqsA. |
| Databáze: | OpenAIRE |
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