| Autor: |
Pankajavalli Thirugnanasambantham, Sravya Kovvali, Austin Cool, Yuan Gao, Anice Sabag-Daigle, Erin F. Boulanger, Mark Mitton-Fry, Angela Di Capua, Edward J. Behrman, Vicki H. Wysocki, Steffen Lindert, Brian M. M. Ahmer, Venkat Gopalan |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Pathogens, Vol 11, Iss 10, p 1102 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2076-0817 |
| DOI: |
10.3390/pathogens11101102 |
| Popis: |
Although salmonellosis, an infectious disease, is a significant global healthcare burden, there are no Salmonella-specific vaccines or therapeutics for humans. Motivated by our finding that FraB, a Salmonella deglycase responsible for fructose-asparagine catabolism, is a viable drug target, we initiated experimental and computational efforts to identify inhibitors of FraB. To this end, our recent high-throughput screening initiative yielded almost exclusively uncompetitive inhibitors of FraB. In parallel with this advance, we report here how a separate structural and computational biology investigation of FrlB, a FraB paralog, led to the serendipitous discovery that 2-deoxy-6-phosphogluconate is a competitive inhibitor of FraB (KI ~ 3 μM). However, this compound was ineffective in inhibiting the growth of Salmonella in a liquid culture. In addition to poor uptake, cellular metabolic transformations by a Salmonella dehydrogenase and different phosphatases likely undermined the efficacy of 2-deoxy-6-phosphogluconate in live-cell assays. These insights inform our ongoing efforts to synthesize non-hydrolyzable/-metabolizable analogs of 2-deoxy-6-phosphogluconate. We showcase our findings largely to (re)emphasize the role of serendipity and the importance of multi-pronged approaches in drug discovery. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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