Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug Target
Although salmonellosis, an infectious disease, is a significant global healthcare burden, there are no <i>Salmonella</i>-specific vaccines or therapeutics for humans. Motivated by our finding that FraB, a <i>Salmonella</i> deglycase responsible for fructose-asparagine catabol...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Pathogens |
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| Online Access: | https://www.mdpi.com/2076-0817/11/10/1102 |
| _version_ | 1797470556701851648 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Pankajavalli Thirugnanasambantham |
| collection | DOAJ |
| description | Although salmonellosis, an infectious disease, is a significant global healthcare burden, there are no <i>Salmonella</i>-specific vaccines or therapeutics for humans. Motivated by our finding that FraB, a <i>Salmonella</i> 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<sub>I</sub> ~ 3 μM). However, this compound was ineffective in inhibiting the growth of <i>Salmonella</i> in a liquid culture. In addition to poor uptake, cellular metabolic transformations by a <i>Salmonella</i> 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. |
| first_indexed | 2024-03-09T19:37:53Z |
| format | Article |
| id | doaj.art-c280ab1c7e0c4598b514097154172a76 |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-09T19:37:53Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-c280ab1c7e0c4598b514097154172a762023-11-24T01:47:44ZengMDPI AGPathogens2076-08172022-09-011110110210.3390/pathogens11101102Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug TargetPankajavalli Thirugnanasambantham0Sravya Kovvali1Austin Cool2Yuan Gao3Anice Sabag-Daigle4Erin F. Boulanger5Mark Mitton-Fry6Angela Di Capua7Edward J. Behrman8Vicki H. Wysocki9Steffen Lindert10Brian M. M. Ahmer11Venkat Gopalan12Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USADepartment of Microbiology, The Ohio State University, Columbus, OH 43210, USADepartment of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USADepartment of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USADepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USADepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USADepartment of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH 43210, USADepartment of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USADepartment of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USADepartment of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USADepartment of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USADepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USADepartment of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USAAlthough salmonellosis, an infectious disease, is a significant global healthcare burden, there are no <i>Salmonella</i>-specific vaccines or therapeutics for humans. Motivated by our finding that FraB, a <i>Salmonella</i> 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<sub>I</sub> ~ 3 μM). However, this compound was ineffective in inhibiting the growth of <i>Salmonella</i> in a liquid culture. In addition to poor uptake, cellular metabolic transformations by a <i>Salmonella</i> 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.https://www.mdpi.com/2076-0817/11/10/1102<i>Salmonella</i> deglycasedrug discoverycompetitive inhibitorserendipity |
| spellingShingle | 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 Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug Target Pathogens <i>Salmonella</i> deglycase drug discovery competitive inhibitor serendipity |
| title | Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug Target |
| title_full | Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug Target |
| title_fullStr | Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug Target |
| title_full_unstemmed | Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug Target |
| title_short | Serendipitous Discovery of a Competitive Inhibitor of FraB, a <i>Salmonella</i> Deglycase and Drug Target |
| title_sort | serendipitous discovery of a competitive inhibitor of frab a i salmonella i deglycase and drug target |
| topic | <i>Salmonella</i> deglycase drug discovery competitive inhibitor serendipity |
| url | https://www.mdpi.com/2076-0817/11/10/1102 |
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