Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Malcolm S. Cole; Michael D. Howe; Joseph A. Buonomo; Sachin Sharma; Elise A. Lamont; Scott I. Brody; Neeraj K. Mishra; Yusuke Minato; Joshua M. Thiede; Anthony D. Baughn; Courtney C. Aldrich

doi:10.1002/chem.202200995

Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Malcolm S. Cole, Michael D. Howe, Joseph A. Buonomo, Sachin Sharma, Elise A. Lamont, Scott I. Brody, Neeraj K. Mishra, Yusuke Minato, Joshua M. Thiede, Anthony D. Baughn, Courtney C. Aldrich

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

3 Scopus citations

Abstract

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.

Original language	English (US)
Article number	e202200995
Journal	Chemistry - A European Journal
Volume	28
Issue number	51
DOIs	https://doi.org/10.1002/chem.202200995
State	Published - Sep 12 2022

Bibliographical note

Funding Information:
This work was supported by a grant (5R21AI144501‐02 to C.C.A. and A.D.B.) from the National Institutes of Health. Mass spectrometry was carried out with the assistance of Dr. Bruce A. Witthuhn (College of Biological Sciences, University of Minnesota). The pET28‐ plasmid used for transformation was a gift from Dr. John S. Blanchard (Department of Biochemistry, Albert Einstein College of Medicine). M.S.C. received funding from The 3 M Company and the National Institutes of Health (5T32 GM008700‐18). J.A.B. was supported by a Bighley Fellowship (College of Pharmacy, University of Minnesota) and the National Science Foundation (GRFP 00039202). blaC E. coli

Funding Information:
This work was supported by a grant (5R21AI144501-02 to C.C.A. and A.D.B.) from the National Institutes of Health. Mass spectrometry was carried out with the assistance of Dr. Bruce A. Witthuhn (College of Biological Sciences, University of Minnesota). The pET28-blaC plasmid used for E. coli transformation was a gift from Dr. John S. Blanchard (Department of Biochemistry, Albert Einstein College of Medicine). M.S.C. received funding from The 3 M Company and the National Institutes of Health (5T32 GM008700-18). J.A.B. was supported by a Bighley Fellowship (College of Pharmacy, University of Minnesota) and the National Science Foundation (GRFP 00039202).

Publisher Copyright:
© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

Keywords

beta-lactamase
cephalosporin
mycobacterium tuberculosis
new antibiotics
pyrazinamide

UN SDGs

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

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10.1002/chem.202200995

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title = "Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis",

abstract = "Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.",

keywords = "beta-lactamase, cephalosporin, mycobacterium tuberculosis, new antibiotics, pyrazinamide",

author = "Cole, {Malcolm S.} and Howe, {Michael D.} and Buonomo, {Joseph A.} and Sachin Sharma and Lamont, {Elise A.} and Brody, {Scott I.} and Mishra, {Neeraj K.} and Yusuke Minato and Thiede, {Joshua M.} and Baughn, {Anthony D.} and Aldrich, {Courtney C.}",

note = "Funding Information: This work was supported by a grant (5R21AI144501‐02 to C.C.A. and A.D.B.) from the National Institutes of Health. Mass spectrometry was carried out with the assistance of Dr. Bruce A. Witthuhn (College of Biological Sciences, University of Minnesota). The pET28‐ plasmid used for transformation was a gift from Dr. John S. Blanchard (Department of Biochemistry, Albert Einstein College of Medicine). M.S.C. received funding from The 3 M Company and the National Institutes of Health (5T32 GM008700‐18). J.A.B. was supported by a Bighley Fellowship (College of Pharmacy, University of Minnesota) and the National Science Foundation (GRFP 00039202). blaC E. coli Funding Information: This work was supported by a grant (5R21AI144501-02 to C.C.A. and A.D.B.) from the National Institutes of Health. Mass spectrometry was carried out with the assistance of Dr. Bruce A. Witthuhn (College of Biological Sciences, University of Minnesota). The pET28-blaC plasmid used for E. coli transformation was a gift from Dr. John S. Blanchard (Department of Biochemistry, Albert Einstein College of Medicine). M.S.C. received funding from The 3 M Company and the National Institutes of Health (5T32 GM008700-18). J.A.B. was supported by a Bighley Fellowship (College of Pharmacy, University of Minnesota) and the National Science Foundation (GRFP 00039202). Publisher Copyright: {\textcopyright} 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.",

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AU - Sharma, Sachin

AU - Lamont, Elise A.

AU - Brody, Scott I.

AU - Mishra, Neeraj K.

AU - Minato, Yusuke

AU - Thiede, Joshua M.

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N2 - Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.

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Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Abstract

Bibliographical note

Keywords

UN SDGs

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