Successful small-molecule antibacterial agents must meet a variety of criteria. Foremost is the need for selectivity and safety: It is easy to kill bacteria with chemicals, but difficult to do it without harming the patient. Other requirements are possession of a useful antibacterial spectrum, no cross-resistance with existing therapeutics, low propensity for rapid resistance selection, and pharmacological properties that allow effective systemic dosing. Choosing molecular targets for new antibiotics does seem a good basis for achieving these criteria, but this could be misleading. Although the presence of the target is necessary to insure the desired spectrum, it is not sufficient, as the permeability and efflux properties of various species, especially Gram-negatives, are critical determinants of antibacterial activity. Further, although essentiality (at least in vitro), lack of close human homologs, lack of target-based cross-resistance, and presence in important pathogens can be predicted based on the target, the choice of a single enzyme as a target may increase the likelihood of rapid resistance selection. In fact, it is likely that the low output of antibacterial target-based discovery is because of difficulty of endowing lead enzyme inhibitors with whole-cell activity and to the propensity for such inhibitors (if they can gain entry) to select rapidly for resistance. These potential problems must be reckoned with for success of novel target-based discovery.
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