Uncovering the killing-mechanism of bactericidal 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 by the last resort antibiotics Vancomycin and Daptomycin used to treat life-threatening multidrug resistant infections, target the bacterial cell wall synthesis machinery. Aminoglycosides, macrolides and tetracyclines, in turn, target bacterial ribosomes and inhibit the protein translation process. While cell wall-targeting antibiotics are bactericidal, most ribosome-targeting antibiotics are bacteriostatic and, thus, inhibit bacterial growth without killing them. However, aminoglycosides form a striking exception from this trend and are strongly bactericidal through a mechanism that, despite extensive studies, is still not fully understood.

Recently, we made a surprisingly discovery that cell wall-targeting antibiotics and aminoglycosides share a previously unrecognised antibacterial mode of action that contributes to their ability to induce rapid bacterial killing. Studying this newly identified cellular process will provide exciting insights into the core mechanisms that allow antibiotics to kill their target bacteria. This is important in order to understand how existing and widely used antibiotic classes work, but also to decipher why they share a comparatively low rate of antibiotic resistance (AMR) development. Hence, studying these processes will allow us to guide the development of the next generation of new antibiotics towards ones with intrinsically lower risk of resistance development.

In this collaborative project between the groups of Henrik Strahl and Kevin Waldron (Newcastle) and Gary Sharples (Durham), the newly discovered mode of action shared by cell wall and aminoglycoside antibiotics will be analysed using the Gram-positive model organism Bacillus subtilis and the model pathogen Staphylococcus aureus. The research programme makes extensive use of advanced microscopy techniques such as microfluidic devises, super resolution microscopy and high-speed imaging. The student will, thus, enjoy an exceptionally broad training in state-of-the-art methods in molecular and cellular microbiology, and in antibiotic research.