Antibiotics have enabled a revolution in human health, however their use is now at a crisis point due to bacterial resistance to even the latest antibiotics. Linezolid, a member of the oxazolidinone family of antibiotics, is a relatively new drug, whose action involves preventing protein translation by binding at in the active site of the bacterial ribosome; the peptidyl transferase center (PTC).
Our research interest is in utilising the latest tools in structural biology to more fully capture the nature of the PTC. We are achieving this by analysing the cryoEM structures of the 70S ribosome from multiple species of bacteria Staphylococci and Enterococci (including clinical linezolid resistant strains). Taken all together this data has led us to propose a range of chemical modifications to linezolid which should increase ribosome affinity and overcome some of the problems of resistance.
This strategy has proved to be successful with two members of our first library of fully synthetic derivatives of linezolid showing increased affinity to both the Staph. and Enterococcus. ribosomes which is mirrored in their increased capacity to inhibit bacterial growth as measured in broth dilution MIC experiments. These redesigned drugs are more potent, but also remain active against strains of bacteria which are resistant to linezolid, the parent antibiotic.
Not only have we rationally redesigned this class of antibiotics in this 'proof of principle' experiment but have also collected high resolution cryoEM data of the new lead oxazolidinone drug in complex with the 70S bacterial ribosome, confirming our hypothesis on drug binding.