Structures of resistance-breaking derivatives of established antibiotic classes. Selected compounds are depicted that were recently launched or are currently in development. Ceftobiprole has increased affinity for PBP2a, a member of the target family of penicillin-binding proteins not affected by marketed β-lactams. Tigecycline, iclaprim, telithromycin, and telavancin make contacts to additional binding sites on their established targets or address additional targets. Structural elements responsible for the novel target interactions are marked bold. MCB-3681, TD-1792, and CBR-2092 are hybrid molecules, in which two pharmacophors from different antibiotic classes are attached by linkers. Linkers are marked bold

All antibiotics that have been successfully employed for decades as monotherapeutics in the treatment of bacterial infections rely on mechanisms of bacterial growth inhibition which are by far more complex than inhibition of a single enzyme. Such successful antibiotics have in common that they address several targets in parallel and/or that their targets are encoded by multiple genes. Such multiplicity of targets and of target genes has the advantage that the emergence of spontaneous target-related resistance is a comparatively slow process. Recently registered antibiotics and novel antibiotics in development are discussed in the light of this promising concept of antibacterial polypharmacology.

How many modes of action should an antibiotic have?

• Heike Brötz-Oesterhelt 
• Nina A Brunner 

• AiCuris GmbH & Co.KG, Friedrich-Ebert Strasse 475, Building 302, D-42117 Wuppertal, Germany

Available online 30 July 2008

• http://dx.doi.org/10.1016/j.coph.2008.06.008,

http://www.sciencedirect.com/science/article/pii/S1471489208000799