Compounds of the γ-carboline family inhibit trans -translation

BACKGROUND AND OBJECTIVES: Because antimicrobial resistance is one of the most pressing global health challenges of our time, it is crucial to find and develop new antimicrobial compounds, especially molecules with new targets and mechanisms of action. Among those, trans-translation, the main quality control system responsible for rescuing bacterial ribosomes present in non-stop complexes, is an appealing target. The objective of this study was to use in vitro and in vivo screening assays to evaluate organic compounds from the French Essential Chemical Library (Chimiothèque Nationale Essentielle, CNE) as trans-translation inhibitors. METHODS: In vitro cell-free assays and whole-cell in vivo trans-translation assays were performed to screen compounds from the chemical library. MIC and chequerboard assays were performed to assess the compounds' inhibition of bacterial cell growth in ESKAPE pathogens, alone or in combination with current antibiotics. RESULTS: Our initial results revealed a new family of γ-carboline compounds capable of inhibiting trans-translation in both in vitro and in vivo Escherichia coli-based assays, without affecting canonical translation. One molecule from the γ-carboline family, namely compound 404, presented high activity and specificity. CONCLUSIONS: These findings raise the prospect of further optimization of γ-carboline compounds' activity in order to use them in combination with currently available antibiotics to combat resistant pathogenic bacteria.