Antibiotic resistance threatens to throw mankind back into an era when infectious disease was the predominant cause of death. In an effort to mitigate this danger, we targeted ErmC’ and KsgA. Both methylate N6-adenosine of ribosomal RNA, though each serve different roles in their bacterial host. ErmC’ dimethylates A2058 on 23S rRNA, conferring resistance to MLSB antibiotics (macrolides, lincosamides, streptogramin B). KsgA aids in ribosome assembly, binding inactive 30S until dimethylating A1518/A1519 of 16S rRNA. Like most methyltransferases, ErmC’ and KsgA use cofactor S-adenosylmethionine (SAM) as their methyl source, which binds adjacent to their specific adenosine substrate. ErmC’ inhibitors could restore MLSB antibiotics against infections with this resistance mechanism. KsgA inhibitors could form novel antibiotics that stall 30S assembly. Previous studies reported a potent ErmC’ inhibitor, N6-cyclopentyl adenosine (1), binding to the substrate pocket with cyclopentyl bridging into the SAM pocket. We expanded this study by synthesizing 1 and 22 other N6-substituted analogs to explore more favorable interactions within the SAM pocket. When these compounds (1mM) were screened against ErmC’ and KsgA, some showed greater inhibition than 1. Two of these inhibitors that were crystallized with ErmC’, N6-8-octylamine adenosine (2.60Å) and N6-phenethyl adenosine (2.40Å), unexpectedly docked into the SAM pocket with their 5’-C pointing towards the substrate pocket. New compounds were made to exploit this orientation by adding substituents off the 5’-C to probe the substrate pocket. Through a five step synthesis, the 5’-OH of 1 was substituted with an amine linked to benzyl (30), phenethyl (31), propylphenyl (32) or butylphenyl (33). When 30-33 were screened using 20μM SAM, ErmC’ showed greater inhibition (relative to 1), while KsgA showed virtually none. However, when ErmC’ was tested using 0.5μM SAM, inhibition from 30-33 was nearly unchanged, whereas 1 became significantly more potent than 30-33, suggesting 30-33 were not binding to the SAM pocket. Preliminary data showed that raising 23S concentrations lowered inhibition from 32-33, while inhibition from 1, 30 and 31 was nearly unchanged, suggesting that at least 32-33 bound within the substrate pocket.