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Synthesis and Evaluation of Acridone and Xanthone Epoxides with Anti-MRSA and Anti-MSSA Activity

Chittepu, P.; Yang, J.; Benoit, A.; Salomon, C. E.; Ji, Y.; Ferguson, D. M.

2021-12-14 microbiology
10.1101/2021.12.10.472175 bioRxiv
Show abstract

A series of acridone and xanthone-based compounds bearing 1,2-epoxypropyl or 1,2-propanediol substituents were synthesized and evaluated for activity against MRSA and MSSA bacterial strains. The results indicate a correlation exists between the number of epoxide groups and activity, with peak MIC values observed for bis-epoxy derivatives. Both activity and heathy cell toxicity was shown to decrease with the addition of a third epoxy group. The corresponding ring-opened diol analogs were devoid of activity, demonstrating the critical function of the epoxide in mediating antimicrobial activity. The most active compounds were also screened using a regulated antisense RNA expression library. The results show no increase in activity against cells sensitized by down-regulation of the most common drug targets, including DNA gyrase, DNA topoisomerase, tRNA synthetase, and the fatty acid biosynthesis pathway. The compounds are postulated to function as membrane disrupting agents, similar to the xanthone natural product -mangostin.

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