Tackling antimicrobial resistance (AMR) using single particle cryoEM

Belousoff MJ1, Yonath A3, Lupton D2 and Lithgow T1

  1. School of Microbiology, Monash University.
  2. School of Chemistry, Monash University.
  3. Weizmann Institute of Science, Israel.

The World Health Organization states that by 2050, deaths from antibiotic or drug-resistant microbes could exceed all other current global health risks. These predictions rest on the assumption that there will be no new treatments come to the clinic. Our lab is determined to tackle a facet of the AMR problem by exploring an important target of antimicrobials; the bacterial ribosome. Ribosomal interfering antibiotics are used to commonly treat serious infections by methicillin resistant S. aureus (MRSA) and vancomycin resistant Enterococcus (VRE). One of the more effective ribosomal interfering antibiotics is the first fully synthetically produced antimicrobial; linezolid. Our work attempts to address two main questions: is it possible to understand how bacteria modify their ribosomal structure as they evolve linezolid resistance and is it possible to use this structural information to redesign the linezolid chemical structure to keep it active against resistant strains of bacteria? I will present the structure of the MRSA ribosome and the structure from a clinical isolate from the Alfred hospital which became resistant to linezolid during the course of treatment [1]. Our cryoEM studies clearly show how the binding site of the antibiotic is drastically remodeled due to a single point mutation in the resistant Staph. strain. Using the structural information as to how MRSA evades linezolid treatment we rationally redesigned linezolid and chemically synthesised new antibiotic derivatives which remained active against the linezolid resistant strains of Staph. Moreover, I will present high resolution (2.8 Å resolution) structures of these new drugs in complex with the MRSA ribosome to confirm our rational drug designs. Excitingly, we have shown that utilizing a pragmatic approach to antibiotic design that it is possible to make minor chemical changes to an existing antibiotic platform to keep it active in the face of antibiotic resistance. [1] Matthew J. Belousoff, et al. Structural basis for linezolid binding site rearrangement in the Staphylococcus aureus ribosome. MBio, 2017, 8:e00395-17.