The World Health Organization (WHO) has announced that antibiotic resistance in bacteria has become a global health crisis. Multidrug-resistant <i>Mycobacterium tuberculosis</i> has caused more than 250,000 deaths in 2015. According to the Center for Disease Control and Prevention (CDC), patients in the United States have been prescribed more than 250 million antibiotic doses each year, yet approximately 23,000 annual deaths in the US are caused by multi drug-resistant bacterial infections. Thus, development of novel antibiotics has become a necessity. The goal of our research is to disrupt ribosomal assembly mechanisms by inhibiting ribosomal modification enzymes. Our research is focused on protein RsmC (ribosomal RNA small subunit methyltransferase C), which binds to the 3’ helix 34 (3’-h34) of the 16S 3’-major domain rRNA and methylates a guanine at position 1207 (G1207; <i>E. coli</i> numbering). Transverse mutations at position 1207 resulted in a lethal phenotype, perhaps due to the formation of a nonfunctioning ribosome. We have discovered a 7-mer peptide that binds tightly to 3’-h34 RNA using phage display. Tryptophan quenching experiments confirmed the binding of the peptide to 3’-h34. Furthermore, FRET inhibition assays showed that the peptide inhibits binding of RsmC to its target. This peptide will be further characterized to improve its delivery to bacterial cells as well as its binding affinity to the target RNA.

Discovery and characterization of peptide inhibitors of RsmC function

2019 Spring National Meeting

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