Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus

Skye Travis; Keith D. Green; Nishad Thamban Chandrika; Allan H. Pang; Patrick A. Frantom; Oleg V. Tsodikov; Sylvie Garneau-Tsodikova; Matthew K. Thompson

doi:10.1039/d3md00113j

Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus

Skye Travis, Keith D. Green, Nishad Thamban Chandrika, Allan H. Pang, Patrick A. Frantom, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova, Matthew K. Thompson

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn²⁺-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus, one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus. Our results will inform future studies on inhibitor design for the FosB enzymes.

Original language	English
Pages (from-to)	947-956
Number of pages	10
Journal	RSC Medicinal Chemistry
Volume	14
Issue number	5
DOIs	https://doi.org/10.1039/d3md00113j
State	Published - Apr 24 2023

Bibliographical note

Funding Information:
This work was funded by The University of Alabama startup funds (to M. K. T.), the Cystic Fibrosis Foundation Grant #THOMPS2010 (to M. K. T.), and National Institutes of Health grant #1R15GM148956 (to M. K. T.). S. T. would like to acknowledge the Department of Education GAANN Grant #P200A150329. M. K. T would like to acknowledge the generosity of the Richard N. Armstrong family and Vanderbilt University Department of Biochemistry for initial laboratory equipment along with plasmids and reagents specific to this project. We thank the staff of the SER-CAT sector at the Advanced Photon Source at the Argonne National Laboratory for assistance with remote data collection and the University of Kentucky Center for Structural Biology for the synchrotron support. The Hek-293 are from ATCC (ATCC CRL-1573), the HepG2 from ATCC (ATCC HB-8065). Some NMR data reported in this publication were recorded on a Bruker AVANCE NEO 600 MHz high-performance digital NMR spectrometer supported by a NIH S10 grant S10OD028690 (to S. G.-T.). We thank the University of Kentucky PharmNMR Center (in the College of Pharmacy) for NMR support.

Publisher Copyright:
© The Royal Society of Chemistry 2023.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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title = "Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus",

abstract = "Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn2+-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus, one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus. Our results will inform future studies on inhibitor design for the FosB enzymes.",

author = "Skye Travis and Green, {Keith D.} and {Thamban Chandrika}, Nishad and Pang, {Allan H.} and Frantom, {Patrick A.} and Tsodikov, {Oleg V.} and Sylvie Garneau-Tsodikova and Thompson, {Matthew K.}",

note = "Funding Information: This work was funded by The University of Alabama startup funds (to M. K. T.), the Cystic Fibrosis Foundation Grant #THOMPS2010 (to M. K. T.), and National Institutes of Health grant #1R15GM148956 (to M. K. T.). S. T. would like to acknowledge the Department of Education GAANN Grant #P200A150329. M. K. T would like to acknowledge the generosity of the Richard N. Armstrong family and Vanderbilt University Department of Biochemistry for initial laboratory equipment along with plasmids and reagents specific to this project. We thank the staff of the SER-CAT sector at the Advanced Photon Source at the Argonne National Laboratory for assistance with remote data collection and the University of Kentucky Center for Structural Biology for the synchrotron support. The Hek-293 are from ATCC (ATCC CRL-1573), the HepG2 from ATCC (ATCC HB-8065). Some NMR data reported in this publication were recorded on a Bruker AVANCE NEO 600 MHz high-performance digital NMR spectrometer supported by a NIH S10 grant S10OD028690 (to S. G.-T.). We thank the University of Kentucky PharmNMR Center (in the College of Pharmacy) for NMR support. Publisher Copyright: {\textcopyright} The Royal Society of Chemistry 2023.",

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AU - Frantom, Patrick A.

AU - Tsodikov, Oleg V.

AU - Garneau-Tsodikova, Sylvie

AU - Thompson, Matthew K.

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N2 - Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn2+-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus, one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus. Our results will inform future studies on inhibitor design for the FosB enzymes.

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Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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