Mechanisms for antibiotic tolerance and envelope remodeling in Gram-negative bacteria

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This collaboration between Elitza Tocheva at the University of British Columbia and Tobias Dörr at Cornell University seeks to elucidate mechanisms of bacterial envelope morphogenesis and antibiotic tolerance while providing quality training to their research teams. The diverse Gram-negative bacteria at the center of this research display a robust ability to survive catastrophic envelope damage and the loss of their cell walls. These bacteria can compensate for cell wall deficiency until the damaging agent, i.e., a cell wall-acting antibiotic like penicillin, is removed and they can regenerate their cell walls. This phenomenon is termed "antibiotic tolerance." As the bacterial cell wall is the target of several classes of antibiotics, it is critical that we understand the mechanisms that permit these tolerant bacteria to survive cell wall-targeting antibiotics. Observing the recovery of these tolerant bacteria from a cell wall-deficient state back to a walled state also presents an opportunity to tackle the elusive yet fundamental question of how rod-shaped bacteria establish their cell shape without the template of a pre-existing cell wall. The Tocheva and Dörr groups will apply a unique and powerful combination of advanced, high-resolution cryo-electron tomography, genetics, and biochemistry to these understudied and historically difficult research questions. Genetic screens performed by the Dörr lab in V. cholerae, E. cloacae, and K. pneumoniae have identified key bacterial stress response systems and envelope biogenesis pathways that contribute to antibiotic tolerance. These studies are the source of numerous hypotheses regarding the roles of each layer in the Gram-negative bacterial envelope during cell wall degradation and regeneration that will be probed by the Tocheva lab via cryo-electron tomography and correlative fluorescent microscopy techniques. This trainee-driven project will establish Canadian expertise in both fundamental bacteriology and the emerging field of antibiotic tolerance.