Lysis-independent killing by cell wall-targeting antibiotics


Event details

Date 13.12.2022 12:1513:15  
Speaker Henrik Strahl, Centre for Bacterial Cell Biology, Newcastle University, UK
Category Conferences - Seminars
Event Language English

Antibiotics that target different steps of bacterial cell wall synthesis such as beta-lactams, vancomycin, and fosfomycin are generally assumed to induce cell lysis as their core antibacterial mode of action. This bacteriolytic process is catalysed by cell’s own wall-degrading enzymes (autolysins) that degrade peptidoglycan in an uncontrollable manner upon inhibition of cell wall synthesis. This runaway degradation leads to weakening of the cell wall sacculus until the cells are no longer able to withstand turgor and undergo lysis. However, cell lysis is insufficient to explain the rapid killing observed in Gram-positive bacteria with a thick cell wall. In fact, Gram-positive bacteria frequently lose viability at a much faster rate than they lyse. To study the cellular mechanisms behind the rapid, lysis-independent killing in Gram-positives, we analysed the mode of action of cell wall antibiotics at a single-cell level using predominantly fluorescence microscopic techniques. Our experiments carried out with Bacillus subtilis and Staphylococcus aureus revealed that inhibition of cell wall synthesis, surprisingly, triggers depolarisation of the cytoplasmic membrane that precedes and is independent of the lysis process. Using various fluorescence reporters and cellular assays, we found that the membrane depolarisation induced by cell wall-targeting antibiotics leads to energy starvation, extensive disturbances of cellular spatial organisation, and production of reactive oxygen species (ROS) that is accompanied by protein, lipid and DNA damage. These findings suggest that, rather than being a relatively simple process linked to osmotic lysis, the bactericidal activity of cell wall-targeting antibiotics is a complex cellular phenomenon that integrates autolysin-catalysed bacteriolysis with severe cellular disturbances and damages triggered by membrane depolarisation.

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