Antibiotic resistance is a global pandemic that has emerged as a silent killer. Bacteria have harnessed several mechanisms to evade the effect of antibiotics with drug target modification being a highly efficient strategy utilized by pathogenic systems to render themselves resistant to antibiotics. The ribosome owing to its integral role as the protein synthesis machinery of the cell is a prime target for several antibiotics. Here, we unravel the mechanism of post-transcriptional ribosomal methylation which renders the macrolide lincosamide and streptogramin B ((MLSB) class of antibiotics ineffective. The enzyme Erythromycin-resistance methyltransferases (Erms), exclusively harboured by several multi-drug resistant (MDR) pathogens can site specifically methylate a ribosomal base (A2058, E.coli numbering) in the nascent peptide exit tunnel of the 50S ribosomal subunit which then renders the MDRs resistant to MLSB class of drugs. Interestingly, we show that Erm is an opportunistic enzyme that exclusively targets ribosomal precursors. Using Cryogenic Electron Microscopy (Cryo-EM) we have trapped the Erm-precursor complex and showed how in a complex environment, during ribosomal biogenesis, Erm can methylate its substrate selectively. Moreover, corroborating single molecule FRET measurements were performed to understand the dynamic nature of these interactions and decipher states that the enzyme charters to achieve catalysis. Our work dwells into the unique dual base flipping mechanism employed by Erms to achieve catalysis and have exploited this mechanism to design next generation inhibitors for combination therapy using AI-based drug design facilitating reversal of resistance. We also dwell into design of new semi-synthetic drugs that bypass the resistance machinery itself. Overall, we draw a holistic picture of Erm’s action and delineate methods of curbing its pathogenic function.