Scientists at the Ineos Oxford Institute for antimicrobial research (IOI) have used cutting edge techniques in biochemistry and X-Ray crystallography to understand the binding mode of cefiderocol, an important last-resort antibiotic. The findings published in Chemical Science provide valuable insights for further antibiotic development.
Cefiderocol (Fetroja®) is a recently approved cephalosporin antibiotic used in the treatment of urinary tract infections when other treatment options have failed. It enters into bacterial cells by mimicking molecules released by bacteria, allowing it to bind to iron from the environment. As iron is an essential element needed for bacterial cell function, the binding of cefiderocol to iron allows it to be transported into bacteria via the iron transport system. Once inside the cell, cefiderocol is released and can target proteins in the bacterial cell wall, disrupting cell division which leads to bacterial cell death, thus halting the spread of infection.
Crystals of penicillin binding proteins.
Until now it had been unclear exactly how cefiderocol binds to its target protein within the bacterial cell wall - penicillin binding protein 3 (PBP3). Using a combination of structural biology and biochemistry, IOI scientists obtained the first crystal structure of cefiderocol in complex with PBP3. They looked at the ability of cefiderocol to bind to PBP3 taken from the bacterium Pseudomonas aeruginosa, which can cause serious infections in the lungs and the bloodstream that can be hard to treat due to extensive resistance mechanisms.
The binding mode of cefiderocol was compared to two other cephalosporins – ceftazidime and cefepime – and the carbapenem antibiotic meropenem, which also binds to PBP3. It was identified that during binding of the cephalosporins a side chain is lost, giving valuable insight into the mechanism of action of these compounds. Combining this information with the rate of binding of different compounds to PBP3 it may be possible, with additional work, to further improve the structure of cefiderocol, improving its efficiency to develop a more effective antibiotic.
This work required a combination of biochemistry and X-Ray crystallography. Both techniques were key to inform our understanding of the fragmentation of cefiderocol upon interaction with PBP3. The uptake of cefiderocol via the iron transport system and subsequent binding to the target protein are likely to be responsible for its breadth of activity.
Understanding the detail of how existing antibiotics get into bacteria and exactly how they bind to their target is crucial to develop new antibiotics. This study led by Dr Helen Smith shows for the first time the binding of cefiderocol with its target PBP3. Comparisons with other antibiotics show subtle differences in rates of inhibition, and insights from this work are enabling the design of new antibiotic drugs to combat AMR.
