@article{c8c6eb4029154d749b57637f23f6fd50,
title = "Structure-guided microbial targeting of antistaphylococcal prodrugs",
abstract = "Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs 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, ultimately identifying several promoieties likely to be serum esterase-resistant and microbially labile. These studies will enable structure-guided design of antistaphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.",
author = "Miller, {Justin J.} and Shah, {Ishaan T.} and Jayda Hatten and Yasaman Barekatain and Mueller, {Elizabeth A.} and Moustafa, {Ahmed M.} and Edwards, {Rachel L.} and Dowd, {Cynthia S.} and Planet, {Paul J.} and Muller, {Florian L.} and Jez, {Joseph M.} and John, {Audrey R.Odom}",
note = "Funding Information: We are grateful to the students of the Spring 2020 Biol 4522 course at Washington University for the creation of FrmB point mutation plasmids and the purification of FrmB point mutants. Thank you to Vandna Kukshal and Jason Schaffer for helpful discussions around data and mechanisms, to the Bubeck-Wardenburg laboratory for sharing benchspace during revisions, and to Petra Levin for assistance with microfluidics and microscopy. Fluorescent ester compounds were generously provided by the laboratory of Geoffrey Hoops (Butler University). AOJ is supported by NIH/NIAID R01-AI103280, R21-AI123808, and R21-AI130584, and AOJ is an Investigator in the Pathogenesis of Infectious Diseases (PATH) of the Burroughs Wellcome Fund. This publication was made possible in part by Grant Number UL1 RR024992 from the NIH-National Center for Research Resources (NCRR). Publisher Copyright: {\textcopyright} Miller et al.",
year = "2021",
month = jul,
doi = "10.7554/eLife.66657",
language = "English",
volume = "10",
journal = "eLife",
issn = "2050-084X",
}