Multitarget ligands in antibacterial research: progress and opportunities

Resistance to current antibacterial therapies is an inevitability that represents a significant global health concern. Bacteria have the capacity to render all current drug treatments ineffective, which places a demand on the drug discovery community to constantly develop new antibacterial agents. Compounds that inhibit multiple biological targets, often referred to as multitarget ligands, are an inviting prospect in antibacterial research because, although they will not solve the issue of resistance, they might help to delay the onset.

This review covers some of the recent progress in identifying new ligands that deliberately interact with more than one essential biological target in bacteria. The two principal areas covered are inhibitors of DNA replication and cell wall biosynthesis.

Antibacterial programs for the design of multitarget ligands present an important opportunity for production of antibacterial agents. Their longevity, due to slow development of resistance, is comparable to that seen with other successful agents - but is much improved over single-targeted agents for which resistance can appear in vitro overnight. The preclinical development of these agents will have to overcome the standard problems of antibacterial discovery. Such problems include optimization of characteristics favoring cell entry and particularly the demonstration of selectivity of inhibition of the desired multiple targets without inhibition of other bacterial or any mammalian functions.