Understanding how bacterial cell wall peptidoglycan metabolism can be used to develop antimicrobial strategies

Despite the fact that the progress in developing new antibiotics with novel mechanism of action is limited owing to the considerable challenges involved and the modest financial returns, we are urgently needing new molecules with new mode of actions to overcome the increasing burden of multidrug resistance. Half of all antibiotics prescribed for human use target the bacterial cell wall. Targeting the cell wall has many advantages as it is essential for bacterial survival, with many steps readily accessible from the environment to small molecules and despite the success of beta-lactams, the pathway still has many underexploited targets.

Here, we review the limitations and the gaps that remain to be filled and the latest developments in new targets, strategies and drugs aimed at inhibiting the assembly of a viable cell wall, as this pathway remains a formidable and accessible source of new targets.

The future of the field should benefit immensely from computational and AI-driven methodologies, combinatorial therapies reducing the risk of development of resistance and acknowledging that we have been screening poorly adapted chemical spaces for antibiotic discovery.