Mechanistic understanding of cell wall biosynthesis to combat AMR

Amongst the antibiotics that have been a mainstay of human healthcare for >70 years, the penicillins and successive generations of β-lactams (e.g. cephalosporins, monobactams and carbapenems) have been by far the most used.

These antibiotics target the final stage of bacterial cell wall peptidoglycan (PG) biosynthesis.

PG is polymerized by the activities of penicillin-binding-proteins (PBPs), which harbour multiple poorly- or un-characterised domains.

Despite the undisputed importance of β-lactam antibiotics, we know little about how PBPs interact with their natural substrates. Importantly, we do not know the β-lactam binding kinetics in the presence of different natural substrates, or precisely how these antibiotics kill cells.

Addressing these knowledge gaps is now crucial, as resistance to β-lactams has emerged due to acquisition of enzymes that destroy the antibiotic (β-lactamases), permeability changes in the outer membrane of Gram negative bacteria, or by altering the target itself (arising by horizontal gene transfer).

An integrated, multi-centre, multidisciplinary research programme

We aim to build a UK hub of activity in cell wall biosynthesis that will develop mechanistic insights that open up new ways to target PBPs, including circumventing the current resistance mechanisms.

Our specific aims are to:

1. Decipher the fundamental mechanisms of PBPs at the structural and functional levels

2. Determine how PBP activity is controlled, at the molecular level, by their interaction with other components in vitro and in vivo

3. Extend the new mechanistic insights to understand how subfamilies of β-lactams interfere with PG assembly in vivo and in vitro.

Our industry partners will run screens to identify non-lactam PBP inhibitors alongside our pilot chemistry project to characterise and synthesise novel non-lactam inhibitors.

The SWON Alliance is a £3.2M MRC-funded partnership between Sheffield, Warwick, Oxford and Newcastle to investigate a vital link in the chain of antimicrobial resistance – the bacterial cell wall.