Metabolic theories of Whipple disease

Whipple disease is a rare, infectious, disease first described from a single case by Whipple in 1907. As well as characterising the clinical and pathological features of the condition, Whipple made two suggestions regarding its aetiology. These were either than the disease was caused by an infectious agent, or that it was of metabolic origin. As the disease is now thought to be caused by infection with the bacterium Tropheryma whipplei, historical reviews of the history of the disease typically mention only the first of these suggestions. In this paper, we therefore revisit Whipple’s other theory. We argue that a diverse and often successful research programme was developed around this mechanism of disease causation which gave rise to many useful findings on the condition. In the later parts of this article, we then turn to discuss the surprising neglect of this period of Whipple disease research in the current literature, and conclude by offering a brief reconstruction of this early history suitable for use in a technical context

Discovery of novel, co-factor specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

Millions of individuals are infected with and die from tuberculosis (TB) each year. There is an increasing prevalence of multi-drug resistant (MDR) strains of TB. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid which inhibits the essential NADH-dependent enoyl-ACP reductase, InhA. Isoniazid requires activation by the catalase-peroxidase KatG in order to inhibit InhA. Isoniazid resistance is primarily linked to mutations in the katG gene. Discovery of novel InhA inhibitors which do not require KatG activation is crucial to combating MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, these efforts, despite achieving high potency against the enzyme, have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple novel classes of InhA inhibitors with cell based activity. The utilization of DEX screening allowed for the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed for the identification of co-factor specific inhibitors of InhA which do not require activation by KatG, many of which had bactericidal activity in cell-based assays