Inborn errors of metabolism (IEM) represent a growing group of monogenic disorders each associated with inherited defects in a metabolic enzyme or regulatory protein, leading to biochemical abnormalities arising from a metabolic block. Despite the well-established genetic linkage, pathophysiology and clinical manifestations for many IEMs, there remains a lack of transformative therapy. The available treatment and management options for a few IEMs are often ineffective or expensive, incurring a significant burden to individual, family, and society. The lack of IEM therapies, in large part, relates to the conceptual challenge that IEMs are loss-of-function defects arising from the defective enzyme, rendering pharmacologic rescue difficult. An emerging approach that holds promise and is the subject of a flurry of pre-/clinical applications, is substrate reduction therapy (SRT). SRT addresses a common IEM phenotype associated with toxic accumulation of substrate from the defective enzyme, by inhibiting the formation of the substrate instead of directly repairing the defective enzyme. This minireview will summarize recent highlights towards the development of emerging SRT, with focussed attention towards repurposing of currently approved drugs, approaches to validate novel targets and screen for hit molecules, as well as emerging advances in gene silencing as a therapeutic modality.

The rapid emergence of antibiotic-resistant bacterial strains has prompted efforts to find new and more efficacious treatment strategies. Targeting virulence factors produced by pathogenic bacteria has gained particular attention in the last few years. One of the inherent advantages of this approach is that it provides less selective pressure for the development of resistance mechanisms. In addition, antivirulence drugs could potentially be the answer for diseases in which the use of conventional antibiotics is counterproductive. That is the case for bacterial toxin-mediated diseases, in which the severity of the symptoms is a consequence of the exotoxins produced by the pathogen. Examples of these are haemolytic-uraemic syndrome produced by Shiga toxins, the profuse and dangerous dehydration caused by Cholera toxin or the life-threatening colitis occasioned by clostridial toxins. This review focuses on the recent advances on the development of small molecules with antitoxin activity against Enterohaemorrhagic Escherichia coli , Vibrio cholerae and Clostridium difficile given their epidemiological importance. The present work includes studies of small molecules with antitoxin properties that act directly on the toxin (direct inhibitors) or that act by preventing expression of the toxin (indirect inhibitors).