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validated for drug discovery and may yet succumb to targeted screening (25) . The
fatty acid synthase complex is distinct between bacteria and eukaryotes, and the
finding that triclosan, thiolactomycin, and cerulenin all target components of the
pathway suggest that the pathway should be considered further.
3.6. A Selection of Novel Targets—Innovative Approaches
As described above, the genomic age has resulted in a wealth of gene
products that have been validated as potential targets, at least in terms of
their essential nature and conservation. In many cases, these are the members
of the same well-explored groups highlighted above, but in many others,
newly identified targets have been culled. In addition, as genomics and other
techniques yield a deeper understanding of bacterial physiology and better ways
to manipulate it, researchers are afforded new opportunities to screen against
previously known physiological targets. Certainly not all of the targets currently
under consideration can be vetted here (and not even that subset that has been
divulged to the public), but a selected subset of interest will be touched upon.
Several specific enzymes in different biosynthetic pathways have been
described in terms of potential drug inhibition in the past few years. UDP-
GlcNac deacetylase (LpxC) is a hydrolase critical for the biosynthesis of
lipopolysaccharide lipid A, required for outer membrane synthesis in Gram-
negative bacteria (16) . Several series of compounds have been designed that
relate to the substrate structure, some of which have demonstrated limited
antibacterial activity. More recently, a whole-cell screen has identified sub-
micromolar inhibitors of the enzyme but with limited spectrum. Nevertheless, it
would appear that this target has been validated. Similarly, the enzyme phospho-
pantetheine adenylyltransferase, which catalyzes the last step in the biosynthesis
of the essential molecule CoA, has been investigated as a novel target, in one
case by a high-throughput screen for pyrophosphate release inhibition (26) .
This screen did in fact identify inhibitors of the enzyme; however, the inhibition
did not translate into antibacterial activity (a common obstacle for molecules
identified by in vitro high-throughput screening). An additional pathway being
mined for druggable targets is that of lysine biosynthesis (27) . In bacteria, de
novo lysine synthesis is of course required for protein synthesis, but lysine
is also a critical component of peptidoglycan. The pathway leading to lysine
production is the diaminopimelate pathway and contains steps common to
lysine, threonine, isoleucine, and methionine production. Efforts have been
made to synthesize small inhibitors of several enzymes in the pathway, primarily
as mimics of small amino acid-derived substrates and products. These efforts
 
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