1. Introduction
deaths, autosomal recessive disorder alkaptonuria, hereditary tyrosinaemia
ALKAPTONURIA, HEREDITARY TYROSINAEMIA
Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out. Evaluation of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway, showed that the compound had innate activity against Gram-positive and Gram-negative bacteria, which was lost following conversion into the degradation product benzoquinone acetic acid (BQA). Anti-staphylococcal activity of HGA can be attributed to effects on bacterial membranes. Despite an absence of haemolytic activity, the compound was cytotoxic to human HepG2 cells. We conclude that the antibacterial activity and in vitro safety profile of HGA render it more suitable for use as a topical agent or for inclusion in a small-molecule medicinal chemistry program.The true burden of antimicrobial-resistant (AMR) bacteria has long been speculated. Predictions that 10 million deaths could be associated with AMR bacteria by 2050 are likely to be a significant underestimation [The ultrarare human autosomal recessive disorder alkaptonuria (AKU) is characterised by the absence of homogentisate 1,2-dioxygenase enzyme activity, resulting in overproduction of HGA. Mean circulating concentrations of HGA reach 30.4 ± 0.8 µmol/L in AKU patients in comparison with 2.24 ± 0.25 µmol/L in non-AKU subjects [In 2020, following completion of the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) clinical trial to assess the efficacy of nitisinone in the treatment of AKU, the European Medicines Agency approved nitisinone 10 mg once daily as the first disease-modifying, HGA-lowering therapy. The 4-year parallel-group study, described in detail by Ranganath et al. [Nitisinone has been used to treat hereditary tyrosinaemia type 1 (HT-1) since 1991 [