FtsZ has long been recognized as a potential therapeutic target for the treatment of bacterial infections. Because of the highly conserved nature of this protein across bacterial species, FtsZ inhibitors are thought to have potential as broad-spectrum antibiotics. This idea has led to the discovery, over the last 10 years or so, of several molecules described as having FtsZ inhibitory activity. These compounds are generally thought to target FtsZ because they induce bacterial filamentation (resulting from inhibition of bacillar cell division) and/or have direct effects on FtsZ GTPase activity or polymerization. However, the gold standard for demonstrating target engagement � that is, confirming a direct link between effects on the biochemical activity of the target and on bacterial cell viability � is the ability of a compound to select for resistant clones that contain mutations in the putative target gene, or at least in genes involved in the related pathway(s). This is particularly important for a target like FtsZ for which biochemical assays lack robustness because of the complex and poorly understood interplay between GTPase activity and polymerization, and the requirement for high concentrations of purified FtsZ protein. Compounding the problem is the high rate of resistance emergence that is often associated with single-target agents and in the case of FtsZ, the emerging notion that biochemical activators as well as inhibitors may have antibacterial activity. The story of Merck's efforts to identify potent modulators of FtsZ activity as broad-spectrum antibiotics illustrates the difficulties involved and the importance of demonstrating target engagement as well as understanding the structural basis for compound interactions with FtsZ.

Identification of FtsZ modulators as broad-spectrum antibiotics: Challenges and lessons learned

248th National Meeting (2014)

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