Siderophore conjugates to combat antibiotic-resistant bacteria

Antimicrobial resistance (AMR) is a global threat to society due to the increasing emergence of multi-drug resistant bacteria that are not susceptible to our last line of defence antibiotics. Exacerbating this issue is a severe gap in antibiotic development, with no new clinically relevant classes of antibiotics developed in the last two decades. The combination of the rapidly increasing emergence of resistance and scarcity of new antibiotics in the clinical pipeline means there is an urgent need for new efficacious treatment strategies. One promising solution, known as the 'Trojan horse' approach, hijacks the iron transport system of bacteria to deliver antibiotics directly into cells - effectively tricking bacteria into killing themselves. This transport system uses natively produced siderophores, which are small molecules with a high affinity for iron. By linking antibiotics to siderophores, to make siderophore antibiotic conjugates, the activity of existing antibiotics can potentially be reinvigorated. The success of this strategy was recently exemplified with the clinical release of cefiderocol, a cephalosporin-siderophore conjugate with potent antibacterial activity against carbapenem-resistant and multi-drug resistant Gram-negative bacilli. This review discusses the recent advancements in siderophore antibiotic conjugates and the challenges associated with the design of these compounds that need to be overcome to deliver more efficacious therapeutics. Potential strategies have also been suggested for new generations of siderophore-antibiotics with enhanced activity.

Automated summary

Antimicrobial resistance poses a global threat due to the rise of multi-drug resistant bacteria and the lack of new antibiotics. The 'Trojan horse' approach, which uses bacteria's iron transport system to deliver antibiotics, shows promise in combating this issue. The use of siderophore antibiotic conjugates, such as cefiderocol, has proven to be effective against resistant bacteria. This review discusses recent advancements in these conjugates and the challenges in their design for more efficacious therapies.