D-Serine reduces the expression of the cytopathic genotoxin colibactin.

Some strains harbour the island, a 54 kb genomic island encoding the biosynthesis genes for a genotoxic compound named colibactin. In eukaryotic cells, colibactin can induce DNA damage, cell cycle arrest and chromosomal instability. Production of colibactin has been implicated in the development of colorectal cancer (CRC). In this study, we demonstrate the inhibitory effect of D-Serine on the expression of the island in both prototypic and clinically-associated colibactin-producing strains and determine the implications for cytopathic effects on host cells. We also tested a comprehensive panel of proteinogenic L-amino acids and corresponding D-enantiomers for their ability to modulate transcription. Whilst several D-amino acids exhibited the ability to inhibit expression of , D-Serine exerted the strongest repressing activity (>3.8-fold) and thus, we focussed additional experiments on D-Serine. To investigate the cellular effect, we investigated if repression of colibactin by D-Serine could reduce the cytopathic responses normally observed during infection of HeLa cells with strains. Levels of γ-H2AX (a marker of DNA double strand breaks) were reduced 2.75-fold in cells infected with D-Serine treatment. Moreover, exposure of to D-Serine during infection caused a reduction in cellular senescence that was observable at 72 h post infection. The recent finding of an association between -carrying commensal and CRC, highlights the necessity for the development of colibactin targeting therapeutics. Here we show that D-Serine can reduce expression of colibactin, and inhibit downstream cellular cytopathy, illuminating its potential to prevent colibactin-associated disease.