New (and not so new) antibacterial targets - from where and when will the novel drugs come?

Although the need for new antibacterial therapies and strategies is greater than it has been in a quarter of a century and despite considerable effort, little progress has been observed in the development of agents. Target-based screening for new antibacterial agents has been particularly disappointing, despite a plethora of potential targets, enhanced screening methodologies and considerable investment. Recent efforts are coalescing around tried and true biosynthetic pathways like cell wall biosynthesis and the less well exploited pathway for fatty acid biosynthesis. Novel crystal structures for components of the replication complex and the ribosome have fuelled efforts at screening for novel replication and translation inhibitors. And target-based screening appears to have scored at least a modest success with inhibitors of peptide deformylase. More problematic are strategies targeting virulence and regulation of gene expression; despite considerably better understanding of these processes, there is no clear path to the use of inhibitors of host-pathogen interactions and/or regulation. In targeting the expression of resistance itself, it appears that staying one step ahead of the beta-lactamases is an overly optimistic goal; the best that can be expected is to avoid falling too far behind. Targeting multidrug efflux pumps may be more edifying in the long run.