Epitranscriptome-based antibiotics and resistance-reversing adjuvant therapies
All forms of RNA in all organisms are chemically modified on the nucleobase and sugar moieties, with these RNA modifications – the epitranscriptome – emerging as critical players in bacterial pathogenicity. For example, many bacterial pathogens respond to the stresses of infection and antibiotic treatment with a genetically-programmed entry into a slowly-or non-replicative state accompanied by the formation of a biofilm or, in the case of mycobacteria, a granuloma. The bacteria in this state are typically resistant or tolerant to a broad range of antibiotics (i.e., persistent), with the bacteria reverting to a drug-sensitive state upon removal of the stress. Here we propose to develop resistance-reversing adjuvant drugs that target the RNA-modifying enzymes.
This project builds on our successful development of tRNA methyltransferase inhibitors as antibiotic candidates, making use of an antibiotic development platform created over the past four years. The first target for drug development will be the ribosomal RNA (rRNA) methyltransferases that confer innate and phenotypic resistance to macrolide antibiotics such as erythromycin (ERY). ERY binds to the 23S rRNA at the ribosomal peptide exit tunnel, which stalls translation. ERY resistance methyltransferases (Erm) methylate key nucleotides at the ERY binding site and block drug binding. For example, ErmB is an inducible enzyme that methylates A2058 in 23S rRNA in Ef, S.pneumoniae, and S. aureus, while the analogous Erm37 in M. tuberculosis (Mtb) is constitutively expressed, rendering Mtb innately resistant to ERY. We propose to target ErmB and Erm37 for development of resistance-reversing adjuvant drugs by structure-based design and screening-based discovery in collaboration with microbiologist Kimberly Kline, structural biologist Julien Lescar and medicinal chemist Liu Chuan Fa.