Imbalance between cell biomass production and envelope biosynthesis underpins the bactericidal activity of cell wall -targeting antibiotics

The majority of our clinically most successful antibiotics target surprisingly few cellular processes. The prominent first-line antibiotic-classes penicillins and cephalosporins, but also the last resort antibiotics vancomycin and daptomycin that are used to treat life-threatening multidrug resistant infections, target the bacterial cell wall synthesis machinery. Despite extensive research, how cell wall -targeting antibiotics kill bacteria and why they are clinically so exceptionally successful has remained enigmatic.
The textbook explanation for the bactericidal activity of cell wall -targeting antibiotic is induced cell lysis. However, this ignores the fact that bacteria can die faster than they lyse, and that lysis is frequently not required for efficient killing. Recently, we made the striking discovery that wall-targeting antibiotics trigger a cascade of cellular disturbances that are independent of the induced cell lysis process. Hence, to understand how this prominent class of antibiotics unfolds its antibacterial properties, the cellular processes leading to the lysis-independent killing now needs to be studied in detail.
Studying such processes for known antibiotics is important to truly understand how widely used antibiotic classes work, but also to decipher why they share a comparatively low rate of antimicrobial resistance (AMR) development, a property that is key for their clinically success. Crucially, studying these processes will allow us to guide the development of the next generation of new antibiotics towards cellular targets with intrinsically lower risk of resistance development.
In this closely collaborative project between the groups of Henrik Strahl (Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University) and Rebecca Corrigan (School of Biosciences, University of Sheffield), the newly discovered mode of action of cell targeting antibiotics will be analysed in the Gram-negative model organism Escherichia coli. The research programme makes extensive use of advanced microscopy techniques such as microfluidic devises, super resolution microscopy and high-speed imaging, combined with bacterial genetics, growth dynamics, and antibiotic resistance and stress profiling.