Bacterial defiance as a form of prodrug failure

Brandon Alexander Holt; Gabriel A. Kwong

In our study, insights into bacterial defiance were elucidated in the context of AMP prodrugs that activate by an extracellular mechanism of action. We anticipate that this phenomenon of defiance also extends to prodrugs that are intracellularly activated, which . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/556951 doi: bioRxiv preprint represent the second major category of prodrugs 46 . To account for intracellular activation, our model would include a transport rate term to account for prodrug diffusion across cell membranes 47 . The implications of our model will likely still hold if prodrug transport is not the rate limiting step (i.e., represents a separate mechanism by which bacteria can escape treatment) and is greater than the rate of prodrug activation. This is a reasonable assumption given that the rates of drug 5 diffusion across membranes 48, 49 are on the order 10 10 -10 17 -fold higher than the typical range of prodrug activation rates 50, 51 .