Whole-Cell Hit-to-Lead

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A target-based approach for antibacterial drug discovery (for example, inhibition of a particular enzyme) is one potential strategy toward drug development. A complimentary approach that screens for compounds that inhibit the growth of the organism of interest or a model organism, without any bias toward a particular target, can also be pursued. This program utilizes such an approach. A portion of this work has been published (L. Ballell, et al., ChemMedChem. 2013, 8, 313). Screening of newly acquired compounds against Mtb is continuing. Once identified, cell-active compounds are advanced by medicinal chemistry guided by minimal inhibitory concentration (MIC) assays. After compound discovery and acquisition of some data suggesting that the compound or compound series has promising properties for further development, most researchers view it as desirable to identify the specific molecular target of the compounds, if possible. This should accelerate further lead optimization and would provide information that may be useful for further clinical development activities. Some hits were advanced to the Hit-to-Lead stage (see M. J. Renuinan, et al., PLoS ONE, 2013, 8(4): e60933).