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Title: Potent, specific MEPicides for treatment of zoonotic staphylococci

Abstract

Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not onlymore » substantially increased potency of the inhibitors against staphylococci but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, that DXR represents a promising, druggable target for future development.« less

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); Agency for Healthcare Research and Quality; Burroughs Wellcome Fund; USDOE Office of Science (SC), Biological and Environmental Research (BER); USDNational Institutes of Health (NIH)
OSTI Identifier:
1633492
Alternate Identifier(s):
OSTI ID: 1631899; OSTI ID: 1659281
Grant/Contract Number:  
R01-AI103280; R21-AI123808-01; R01-AI123433; R01-AI097119; T32-AI007172; T32-GM007067; UL1-TR002345; R01-HS021736; R01-HS024269; AC02-06CH11357; 1S10RR022984-01A1; 1S10OD018091-01
Resource Type:
Published Article
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Name: PLoS Pathogens Journal Volume: 16 Journal Issue: 6; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Edwards, Rachel L., Heueck, Isabel, Lee, Soon Goo, Shah, Ishaan T., Miller, Justin J., Jezewski, Andrew J., Mikati, Marwa O., Wang, Xu, Brothers, Robert C., Heidel, Kenneth M., Osbourn, Damon M., Burnham, Carey-Ann D., Alvarez, Sophie, Fritz, Stephanie A., Dowd, Cynthia S., Jez, Joseph M., Odom John, Audrey R., and Yeaman, ed., Michael R. Potent, specific MEPicides for treatment of zoonotic staphylococci. United States: N. p., 2020. Web. doi:10.1371/journal.ppat.1007806.
Edwards, Rachel L., Heueck, Isabel, Lee, Soon Goo, Shah, Ishaan T., Miller, Justin J., Jezewski, Andrew J., Mikati, Marwa O., Wang, Xu, Brothers, Robert C., Heidel, Kenneth M., Osbourn, Damon M., Burnham, Carey-Ann D., Alvarez, Sophie, Fritz, Stephanie A., Dowd, Cynthia S., Jez, Joseph M., Odom John, Audrey R., & Yeaman, ed., Michael R. Potent, specific MEPicides for treatment of zoonotic staphylococci. United States. doi:https://doi.org/10.1371/journal.ppat.1007806
Edwards, Rachel L., Heueck, Isabel, Lee, Soon Goo, Shah, Ishaan T., Miller, Justin J., Jezewski, Andrew J., Mikati, Marwa O., Wang, Xu, Brothers, Robert C., Heidel, Kenneth M., Osbourn, Damon M., Burnham, Carey-Ann D., Alvarez, Sophie, Fritz, Stephanie A., Dowd, Cynthia S., Jez, Joseph M., Odom John, Audrey R., and Yeaman, ed., Michael R. Thu . "Potent, specific MEPicides for treatment of zoonotic staphylococci". United States. doi:https://doi.org/10.1371/journal.ppat.1007806.
@article{osti_1633492,
title = {Potent, specific MEPicides for treatment of zoonotic staphylococci},
author = {Edwards, Rachel L. and Heueck, Isabel and Lee, Soon Goo and Shah, Ishaan T. and Miller, Justin J. and Jezewski, Andrew J. and Mikati, Marwa O. and Wang, Xu and Brothers, Robert C. and Heidel, Kenneth M. and Osbourn, Damon M. and Burnham, Carey-Ann D. and Alvarez, Sophie and Fritz, Stephanie A. and Dowd, Cynthia S. and Jez, Joseph M. and Odom John, Audrey R. and Yeaman, ed., Michael R.},
abstractNote = {Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not only substantially increased potency of the inhibitors against staphylococci but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, that DXR represents a promising, druggable target for future development.},
doi = {10.1371/journal.ppat.1007806},
journal = {PLoS Pathogens},
number = 6,
volume = 16,
place = {United States},
year = {2020},
month = {6}
}

Journal Article:
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DOI: https://doi.org/10.1371/journal.ppat.1007806

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