Antibiotic resistance is a serious problem that affects millions of people worldwide. Different classes of antibiotics target various essential bacterial processes, such as protein synthesis (macrolides), cell wall (penicillins), or DNA replication (quinolones). In response, bacteria can develop resistance, enabling them to survive in the presence of many antibiotics, including those categorized as the last line of defense. In some cases, enzymes are key contributors to the observed resistance. Methyltransferases, which neutralize the antibacterial activity of several classes of antibiotics by methylating ribosomal RNA (rRNA), fall under this category. ErmC is an S-adenosyl-L-methionine (SAM)-dependent methylase that modifies adenine 2058 (A2058) of 23S rRNA through mono or di-methylation of the exocyclic N6 atom, conferring resistance to macrolides, lincosamides, and streptogramins. The research described herein investigates and identifies potential inhibitors of the ErmC activity to hinder the development of resistance in bacterial cells expressing this enzyme. Cell-based screens identified promising compounds that, when combined with macrolide antibiotics, resensitized resistant E. coli cells expressing the Staphylococcus aureus (S. aureus) ErmC.
