Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

Wooseong Kim; Andrew D. Steele; Wenpeng Zhu; Erika E. Csatary; Nico Fricke; Madeline M. Dekarske; Elamparithi Jayamani; Wen Pan; Bumsup Kwon; Isabelle F. Sinitsa; Jake L. Rosen; Annie L. Conery; Beth Burgwyn Fuchs; Petia M. Vlahovska; Frederick M. Ausubel; Huajian Gao; William M. Wuest; Eleftherios Mylonakis

doi:10.1021/acsinfecdis.8b00161

Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

Wooseong Kim, Andrew D. Steele, Wenpeng Zhu, Erika E. Csatary, Nico Fricke, Madeline M. Dekarske, Elamparithi Jayamani, Wen Pan, Bumsup Kwon, Isabelle F. Sinitsa, Jake L. Rosen, Annie L. Conery, Beth Burgwyn Fuchs, Petia M. Vlahovska, Frederick M. Ausubel, Huajian Gao, William M. Wuest, Eleftherios Mylonakis

Pharmaceutical Sciences

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

28 Scopus citations

Abstract

Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides. We improved both the potency and selectivity of nTZDpa against MRSA membranes compared to mammalian membranes by leveraging synthetic chemistry guided by molecular dynamics simulations. These studies provide key insights into the design of selective and potent membrane-active antibiotics effective against bacterial persisters.

Original language	English
Pages (from-to)	1540-1545
Number of pages	6
Journal	ACS Infectious Diseases
Volume	4
Issue number	11
DOIs	https://doi.org/10.1021/acsinfecdis.8b00161
State	Published - 9 Nov 2018

Keywords

MD simulations
MRSA
SAR
antibiotics
membrane-active agent
persisters

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Kim, W., Steele, A. D., Zhu, W., Csatary, E. E., Fricke, N., Dekarske, M. M., Jayamani, E., Pan, W., Kwon, B., Sinitsa, I. F., Rosen, J. L., Conery, A. L., Fuchs, B. B., Vlahovska, P. M., Ausubel, F. M., Gao, H., Wuest, W. M., & Mylonakis, E. (2018). Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters. ACS Infectious Diseases, 4(11), 1540-1545. https://doi.org/10.1021/acsinfecdis.8b00161

@article{26d6d2b9e97d495db8ff26df2b6b5a37,

title = "Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters",

abstract = "Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides. We improved both the potency and selectivity of nTZDpa against MRSA membranes compared to mammalian membranes by leveraging synthetic chemistry guided by molecular dynamics simulations. These studies provide key insights into the design of selective and potent membrane-active antibiotics effective against bacterial persisters.",

keywords = "MD simulations, MRSA, SAR, antibiotics, membrane-active agent, persisters",

author = "Wooseong Kim and Steele, {Andrew D.} and Wenpeng Zhu and Csatary, {Erika E.} and Nico Fricke and Dekarske, {Madeline M.} and Elamparithi Jayamani and Wen Pan and Bumsup Kwon and Sinitsa, {Isabelle F.} and Rosen, {Jake L.} and Conery, {Annie L.} and Fuchs, {Beth Burgwyn} and Vlahovska, {Petia M.} and Ausubel, {Frederick M.} and Huajian Gao and Wuest, {William M.} and Eleftherios Mylonakis",

note = "Funding Information: This study was supported by National Institutes of Health Grant P01 AI083214 to F.M.A. and E.M., by National Science Foundation Grant CMMI-1562904 to H.G., and by National Institute of General Medical Sciences Grant 1R35GM119426 and National Science Foundation Grant NSF1755698 to W.M.W. We thank L. Rice for providing the E. faecium strains. MD simulations were supported by the Extreme Science and Engineering Discovery Environment through Grant MSS090046 and the Center for Computation and Visualization at Brown University. Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = nov,

day = "9",

doi = "10.1021/acsinfecdis.8b00161",

language = "English",

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Kim, W, Steele, AD, Zhu, W, Csatary, EE, Fricke, N, Dekarske, MM, Jayamani, E, Pan, W, Kwon, B, Sinitsa, IF, Rosen, JL, Conery, AL, Fuchs, BB, Vlahovska, PM, Ausubel, FM, Gao, H, Wuest, WM & Mylonakis, E 2018, 'Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters', ACS Infectious Diseases, vol. 4, no. 11, pp. 1540-1545. https://doi.org/10.1021/acsinfecdis.8b00161

TY - JOUR

T1 - Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

AU - Kim, Wooseong

AU - Steele, Andrew D.

AU - Zhu, Wenpeng

AU - Csatary, Erika E.

AU - Fricke, Nico

AU - Dekarske, Madeline M.

AU - Jayamani, Elamparithi

AU - Pan, Wen

AU - Kwon, Bumsup

AU - Sinitsa, Isabelle F.

AU - Rosen, Jake L.

AU - Conery, Annie L.

AU - Fuchs, Beth Burgwyn

AU - Vlahovska, Petia M.

AU - Ausubel, Frederick M.

AU - Gao, Huajian

AU - Wuest, William M.

AU - Mylonakis, Eleftherios

N1 - Funding Information: This study was supported by National Institutes of Health Grant P01 AI083214 to F.M.A. and E.M., by National Science Foundation Grant CMMI-1562904 to H.G., and by National Institute of General Medical Sciences Grant 1R35GM119426 and National Science Foundation Grant NSF1755698 to W.M.W. We thank L. Rice for providing the E. faecium strains. MD simulations were supported by the Extreme Science and Engineering Discovery Environment through Grant MSS090046 and the Center for Computation and Visualization at Brown University. Publisher Copyright: © 2018 American Chemical Society.

PY - 2018/11/9

Y1 - 2018/11/9

N2 - Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides. We improved both the potency and selectivity of nTZDpa against MRSA membranes compared to mammalian membranes by leveraging synthetic chemistry guided by molecular dynamics simulations. These studies provide key insights into the design of selective and potent membrane-active antibiotics effective against bacterial persisters.

AB - Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides. We improved both the potency and selectivity of nTZDpa against MRSA membranes compared to mammalian membranes by leveraging synthetic chemistry guided by molecular dynamics simulations. These studies provide key insights into the design of selective and potent membrane-active antibiotics effective against bacterial persisters.

KW - MD simulations

KW - MRSA

KW - SAR

KW - antibiotics

KW - membrane-active agent

KW - persisters

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U2 - 10.1021/acsinfecdis.8b00161

DO - 10.1021/acsinfecdis.8b00161

M3 - Article

C2 - 30132650

AN - SCOPUS:85052745918

SN - 2373-8227

VL - 4

SP - 1540

EP - 1545

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 11

ER -

Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

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Keywords

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