Bacterial resistance to antibiotics is a serious health concern. If nothing changes in the treatment of infection, it is projected that mortality by bacterial infection will surpass that be cancer and diabetes combined by 2050. What is urgently needed is new insight into the way that bacteria overcome treatment by antibacterials.
In our lab we are undertaking a study into the molecular mechanisms by which two Gram positive hospital pathogens develop resistance to a last line antibiotic; linezolid. We are collecting linezolid resistant strains of both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococcus (VRE) from the Australian clinic. Each strain has its genome sequenced by next-gen Illumina sequencing to determine what mutations have arisen during the antibiotics course.
As the target of linezolid is the bacterial ribosome, each strain has its ribosomes isolated and interrogated by high resolution single particle cryo electron microscopy, to determine the remodelling of the drug binding site due to mutations to the ribosome.
We are starting to uncover a general mechanism whereby multiple types of different mutations in both ribosomal RNA and proteins lead to a similar rearrangement of the linezolid binding pocket. This has led us to propose chemical modifications to the oxazolidinone family (of which linezolid is a member) which may overcome resistance by mutation of the ribosome.