Bacterial cell wall homeostasis and plasticity: from fundamentals to antimicrobial targeting

Bacteria are surrounded by a protective cell wall of peptidoglycan.

This structure has no homolog in human cells, so the enzymes building up the peptidoglycan are preferred targets for many of our most successful antibiotics.

However, emerging resistant infections are threatening the very foundations of modern medicine by eroding the efficacy of our antibiotic arsenal.

Therefore, it is now more important than ever to understand the principles of bacterial cell wall homeostasis and plasticity to find new and more effective methods of targeting it for the treatment of infectious diseases.

Here, I propose a holistic study that combines innovative genome-wide peptidoglycan profiling with chemical genomics and mechanistic characterization to define the repertoire of cell wall genetic determinants in diverse pathogens.

Exploration of mutant libraries will break new ground concerning general and species-specific mechanisms underpinning peptidoglycan homeostasis.

Additionally, by using diverse growth conditions we will learn how bacteria adapt their cell wall to relevant environments (e.g., the host) and which constraints cannot be surpassed in the peptidoglycan structure to preserve viability.

Finally, since the cell wall is one of the major “Achilles heels” of bacteria, this systematic survey of new players in the synthesis and regulation of the peptidoglycan structure has great potential to promote the discovery of new pathways that can be targeted in antimicrobial therapies.