Structure-guided microbial targeting of antistaphylococcal prodrugs

Miller, J.; Shah, I. T.; Hatten, J.; Barekatain, Y.; Mueller, E. A.; Moustafa, A. M.; Edwards, R. L.; Dowd, C. S.; Planet, P. J.; Muller, F. L.; Jez, J. M.; Odom John, A. R.

doi:10.1101/2020.12.15.408237

bioRxiv · 10.1101/2020.12.15.408237

Structure-guided microbial targeting of antistaphylococcal prodrugs

Miller, J.·Shah, I. T.·Hatten, J.·Barekatain, Y.·Mueller, E. A.·Moustafa, A. M.·Edwards, R. L.·Dowd, C. S.·Planet, P. J.·Muller, F. L.·Jez, J. M.·Odom John, A. R.

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Abstract

Carboxy ester prodrugs have been widely employed as a means to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can successfully mask problematic chemical features that prevent cellular uptake and can be used to target delivery of compounds to specific tissues. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, curbing their potential therapeutic applications. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes due to a paucity of information about the selectivity of microbial esterases. Here we identify the bacterial esterases, GloB and FrmB, that are required for carboxy ester prodrug activation in Staphylococcus aureus. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, which revealed several promoieties likely to be serum esterase-resistant while still being microbially labile. These studies lay the groundwork for structure-guided design of anti-staphyloccal promoieties and expand the range of molecules to target staphyloccal pathogens.

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Miller, J., Shah, I. T., Hatten, J., Barekatain, Y., Mueller, E. A., Moustafa, A. M., Edwards, R. L., Dowd, C. S., Planet, P. J., Muller, F. L., Jez, J. M., Odom John, A. R.. 2020-12-15. Structure-guided microbial targeting of antistaphylococcal prodrugs. https://doi.org/10.1101/2020.12.15.408237

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