L-Rhamnose biosynthesis is a ubiquitous pathway in many pathogenic Gram-positive, Gram-negative and mycobacteria. Genetic studies have demonstrated that the pathway contributes significantly to virulence and pathogenicity of many pathogens, including <i>Mycobacterium tuberculosis</i> and the ESKAPE organisms that have developed multi-drug resistance. Rhamnose is a 6-deoxy-L-sugar absent from mammalian cells, and, thus, the biosynthesis of rhamnose offers multiple potential drug targets. The five biochemical steps for L-rhamnose biosynthesis are well documented, with glucose 6-phosphate ultimately being converted to thymdine diphospho rhamnose (TDP-beta-L-Rha). We will discuss rationales for the discovery of inhibitors of the enzymes in rhamnose biosynthesis, and describe the synthetic, chemoenzymatic, computational, enzymological and structural characterization of inhibitors and their targets, and the challenges and successes.

Screening and synthesis of small molecules to inhibit rhamnose biosynthetic enzymes: Towards novel small molecule anti-infectives

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ACS Fall 2022

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