Serendipitous Discovery of a Competitive Inhibitor of FraB, a Salmonella Deglycase and Drug Target.
Serendipitous Discovery of a Competitive Inhibitor of FraB, a Salmonella Deglycase and Drug Target.
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DOI：
10.3390/pathogens11101102
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发表时间：
2022-09-26
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影响因子：
--
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文献类型：
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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.
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影响因子：
4.6
作者：
Sabag-Daigle A;Blunk HM;Sengupta A;Wu J;Bogard AJ;Ali MM;Stahl C;Wysocki VH;Gopalan V;Behrman EJ;Ahmer BM
通讯作者：
Ahmer BM
影响因子：
6.7
作者：
Ali, Mohamed M.;Newsom, David L.;Ahmer, Brian M. M.
通讯作者：
Ahmer, Brian M. M.
影响因子：
2.9
作者：
VANVELDHOVEN, PP;MANNAERTS, GP
通讯作者：
MANNAERTS, GP
影响因子：
8.6
作者：
Bajusz D;Rácz A;Héberger K
通讯作者：
Héberger K
DOI：
10.1016/0167-4838(92)90404-2
发表时间：
1992-08-21
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
HANAU, S;DALLOCCHIO, F;RIPPA, M
通讯作者：
RIPPA, M