Rational selection of anti-microbial drug targets: unique or conserved?

When contemplating a strategy for drug development against an infectious agent such as a bacterium or parasite, there are obvious advantages to choosing a “unique” target in the pathogen. Clearly, inhibition of a pathogen-specific enzyme or pathway that is absent in the mammalian host may be expected to result in fewer adverse effects than inhibition of a highly conserved protein. Yet, through the very definition of a “novel target,” significant practical challenges must be overcome in the drug development process that would likely be less challenging for a pharmacologically well-explored target. The novel target requires much fundamental research before and during the initial screening right through to lead optimization and preclinical toxicity testing. This undoubtedly increases costs substantially, discouraging the involvement of pharmaceutical companies. The alternative paradigm, which we discuss here, is for a well-explored target for which a large body of functional and structural data exists, as well as targeted compound libraries and ADME/Tox data on target modulators. This chapter gives a number of specific examples of anti-parasite drugs in (preclinical) studies that act on conserved targets, and makes the case that this approach may lead to faster development of desperately needed novel and safe anti-parasite therapy