There is a growing burden on human health caused by methicillin resistant Staphylococcus aureus (MRSA). Of even greater concern is that MRSA is developing resistance to further, last-line antimicrobial drugs such as linezolid and daptomycin, abolishing the most pertinent treatment options from the clinic. Structure-informed drug modification represents a frontier to produce new therapies for the clinic. Here we present the cryo-electron microscopy (cryo-EM) structures of three 70S ribosomes from two MRSA strains recently emerged in the clinic and a Staph. aureus strain. We developed facile, rapid methods to derive high-resolution structural information to explain the mechanism by which a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance. Cryo-electron microscopy revealed that while this mutation is located 24 Å away from the linezolid binding pocket (the peptidyl-transferase centre, PTC), it functions by inducing an allosteric structural rearrangement of the rRNA that transmits unexpected widening into the antibiotic binding site, leading to the observed resistance to linezolid.