Bacterial defiance as a form of prodrug failure

Brandon Alexander Holt; Gabriel A. Kwong

The rise of multidrug-resistant bacteria coupled with the lack of newly developed antibiotics has created a serious public health threat 1, 2 . Understanding the causes of antibiotic failure inspires the development of new drugs and informs clinical treatment strategies [3] [4] [5] . These failure mechanisms are broadly classified into three distinct categories (i.e., resistance, 5 persistence, and tolerance), which are characterized by the change in drug concentration and exposure time required to kill bacteria 6 . For example, resistance is characterized by genetic mutations or phenotypic changes which result in bacteria requiring significantly higher concentrations of antibiotic (minimum inhibitory concentration, MIC) to be lethal. By contrast, bacteria exhibiting tolerance or persistence require increased drug exposure time (minimum 10 duration for killing, MDK), with the latter exhibiting a biphasic killing profile (Fig. 1A) . Further, bacteria populations become tolerant through environmental conditions or genetic mutations, whereas persistence is an actively maintained, non-heritable state exhibited by a subpopulation of bacteria. Discriminating between these survival strategies employed by bacteria is crucial for the development of new drugs and clinical treatment decisions 6 . 15