| Autor: |
Thirugnanasambantham P; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA., Kovvali S; Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA., Cool A; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA., Gao Y; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.; Resource for Native Mass Spectrometry-Guided Structural Biology, The Ohio State University, Columbus, OH 43210, USA., Sabag-Daigle A; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA., Boulanger EF; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA., Mitton-Fry M; Department of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA., Capua AD; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.; Resource for Native Mass Spectrometry-Guided Structural Biology, The Ohio State University, Columbus, OH 43210, USA., Behrman EJ; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA., Wysocki VH; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.; Resource for Native Mass Spectrometry-Guided Structural Biology, The Ohio State University, Columbus, OH 43210, USA., Lindert S; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA., Ahmer BMM; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA., Gopalan V; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.; Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA. |
| Abstrakt: |
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 (K I ~ 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. |
