Validated antibacterial targets

Pucci, M.J. 2007. Novel genetic techniques and approaches in the microbial genomics era identification and/or validation of targets for the discovery of new antibacterial agents. Drugs R D 8, 201-212. 

Deformylation of nascent polypeptides has been shown to be a function essential for growth in E. coli, Staphylococcus aureus and Streptococcus pneumoniae [15-18]. Moreover, antibacterial mode of action studies, using S. pneumoniae or S. aureus strains in which the expression of PDF is controlled by regulatable promoters, have shown that the antibacterial activity of PDF inhibitors is due to their inhibition of the PDF enzyme, as the susceptibility of the strains to these compounds is dependent on the amount of protein present in the cell [19-21]. These results further validate PDF as a target for novel antibiotics. 

An interesting exception to the absolute validity of the tifth postulate is the considerable activity of chloramphenicol derivatives in cell-free model systems of protein synthesis when these derivatives are substituted with amino acyl residues instead of with dichloroacetyl as is the antibiotic itself (rev. in 2°)). This has been traced to the necessity of the dichloroacetyl grouping in aiding in the permeation of the antibiotic through the bacterial envelope 21 The amino acyl derivatives have very low antibacterial activity 20. Permeation failures of actinomycin D, macrolides and distamycin A with respect to certain families of bacteria occlude the action of these antibiotics on their intracellular drug receptors and target reactions but can be overcome experimentally by measures which render test organisms permeable. 

Once a target for antibacterial intervention has been selected and validated, a path to obtaining inhibitors must be chosen. Assays can be cell based or in vitro, actual or virtual, and screening methods can be high-throughput, focused, or anywhere in between. The size and type of the net to be cast will determine not only the quantity of hits available for characterization but often will determine the quality and type. 

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