Mechanism-based screens in the discovery of chemotherapeutic antibacterials

Numerous assays have been developed over the last 40 years for the detection of novel antibacterial metabolites. I have discussed many of the successful strategies and suggested some potential targets. Although the trend toward mechanism-based assays is relatively recent, it is clear that they have had a profound impact on screening in drug discovery. Often a mechanism-based assay requires construction of specific strains and verification of the antibacterial role of the selected target. Since the conception and development of a mechanism-based screen depends upon knowledge of the specific target and perhaps a compound that affects that target, it is implicit that mode of action studies on compounds discovered through random screening may subsequently lead to new mechanistic assays. While serendipity continues to play a crucial role in any screen, target-directed assays appear to be a worthwhile approach in antibacterial screening.