The bacterial drug resistance complicated the fight against the infectious diseases and recovery of the patients from the diseases. Major target site for the antibiotic actions is ribosomal region. Bacteria has evolved an elegant, novel epigenetic mode of drug resistance, through the methylation of 23S and 16S ribosomal RNA. The addition of methyl group is favoured by methyltransferase enzymes encoded by different genes. We have evaluated the presence of methyltransferase genes including chloramphenicol/florfenicol cfr  gene which confer drug resistance to five different classes of antibiotics such as oxazolininones, phenicols, lincosamides, pleuromutilins and streptogramin A  in 308 gram positive bacterial isolates. We also studied the presence of methyltransferase genes armA, rmtB, rmtC, rmtD in 200 gram negative bacteria conferring drug resistance to aminoglycosides. These methyltransferases enzymes post transcriptionally methylate residue G1405 of 16S rRNA resulting in high-level resistance to gentamicin, tobramycin, and amikacin.  Our study found the presence of cfr gene in several multidrug resistant Staphylococcus species and concurrent occurrence of armA, rmtB, rmtC, rmtD in several cases of gram negative bacteria including E.coli, Pseudomonas aeruginosa, Klebsiella sp and Acinetobacter Sp.  This study conclude the alarming wide spread occurrence of epigenetic mode of bacterial drug resistance in both gram positive and gram negative bacteria along with other resistant mechanisms. We also evaluated the methylation status of 16S rRNA using RNA bisulfite sequencing.in presence of these methyltransferase genes. We emphasize for screening the presence of these methyltransferase genes for the better surveillance of emerging multi drug resistant bacteria. Further studies are warranted for the global evaluation of presence of these multidrug methyltransferase enzymes to execute the program for the prevention of rapid spread of bacterial drug resistance among community.                                                              
Keywords— Epigenetic mode of drug resistance, Methyltransferase enzymes,  cfr, armA, rmtB, rmtC, rmtD  genes, Bisuflite sequencing