Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens

Ziwei Hu; Inga V. Leus; Brinda Chandar; Bradley S. Sherborne; Quentin P. Avila; Valentin V. Rybenkov; Helen I. Zgurskaya; Adam S. Duerfeldt

doi:10.1021/acs.jmedchem.2c01349

Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens

Ziwei Hu
, Inga V. Leus
, Brinda Chandar
, Bradley S. Sherborne
, Quentin P. Avila
, Valentin V. Rybenkov
, Helen I. Zgurskaya
, Adam S. Duerfeldt

Medicinal Chemistry

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

19 Scopus citations

Abstract

The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species. The results illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogues (3e, 8d, and 8o) were identified that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.

Original language	English (US)
Pages (from-to)	14144-14179
Number of pages	36
Journal	Journal of medicinal chemistry
Volume	65
Issue number	20
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01349
State	Published - Oct 27 2022

Bibliographical note

Funding Information:
This work was supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health (R01AI136795, H.I.Z., V.V.R., and A.S.D.) The content included in this manuscript does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. The authors thank Dr. Alexander S. Mankin for sharing E. coli strains. The authors gratefully acknowledge the collegiality, collaboration, and scientific discussion provided by the other SPEAR-GN team members.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

Publisher link

10.1021/acs.jmedchem.2c01349

Find It

Find It at U of M Libraries

Cite this

@article{cb615d6c632643149f3409c18ef9d79e,

title = "Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens",

abstract = "The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species. The results illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogues (3e, 8d, and 8o) were identified that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.",

author = "Ziwei Hu and Leus, \{Inga V.\} and Brinda Chandar and Sherborne, \{Bradley S.\} and Avila, \{Quentin P.\} and Rybenkov, \{Valentin V.\} and Zgurskaya, \{Helen I.\} and Duerfeldt, \{Adam S.\}",

note = "Funding Information: This work was supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health (R01AI136795, H.I.Z., V.V.R., and A.S.D.) The content included in this manuscript does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. The authors thank Dr. Alexander S. Mankin for sharing E. coli strains. The authors gratefully acknowledge the collegiality, collaboration, and scientific discussion provided by the other SPEAR-GN team members. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

year = "2022",

month = oct,

day = "27",

doi = "10.1021/acs.jmedchem.2c01349",

language = "English (US)",

volume = "65",

pages = "14144--14179",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "20",

}

TY - JOUR

T1 - Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens

AU - Hu, Ziwei

AU - Leus, Inga V.

AU - Chandar, Brinda

AU - Sherborne, Bradley S.

AU - Avila, Quentin P.

AU - Rybenkov, Valentin V.

AU - Zgurskaya, Helen I.

AU - Duerfeldt, Adam S.

N1 - Funding Information: This work was supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health (R01AI136795, H.I.Z., V.V.R., and A.S.D.) The content included in this manuscript does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. The authors thank Dr. Alexander S. Mankin for sharing E. coli strains. The authors gratefully acknowledge the collegiality, collaboration, and scientific discussion provided by the other SPEAR-GN team members. Publisher Copyright: © 2022 American Chemical Society. All rights reserved.

PY - 2022/10/27

Y1 - 2022/10/27

N2 - The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species. The results illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogues (3e, 8d, and 8o) were identified that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.

AB - The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species. The results illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogues (3e, 8d, and 8o) were identified that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.

UR - https://www.scopus.com/pages/publications/85140624493

UR - https://www.scopus.com/pages/publications/85140624493#tab=citedBy

U2 - 10.1021/acs.jmedchem.2c01349

DO - 10.1021/acs.jmedchem.2c01349

M3 - Article

C2 - 36257060

AN - SCOPUS:85140624493

SN - 0022-2623

VL - 65

SP - 14144

EP - 14179

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 20

ER -

Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens

Abstract

Bibliographical note

Publisher link

Find It

Other files and links

Fingerprint

Cite this