Open Access
International Journal of Molecular Sciences, volume 23, issue 3, pages 1834
Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections
Grigorenko V.
1
,
Khrenova Maria G.
1, 2
,
Andreeva Irina P
1
,
Rubtsova Maya
1
,
Lev Anastasia I
3
,
Novikova Tatiana S.
3
,
Dyatlov Ivan A
3
,
Egorov Alexey M.
1
Publication type: Journal Article
Publication date: 2022-02-06
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.6
ISSN: 16616596, 14220067
PubMed ID:
35163756
Catalysis
Organic Chemistry
Inorganic Chemistry
Physical and Theoretical Chemistry
Computer Science Applications
Spectroscopy
Molecular Biology
General Medicine
Abstract
The increasing antibiotic resistance is a clinical problem worldwide. Numerous Gram-negative bacteria have already become resistant to the most widely used class of antibacterial drugs, β-lactams. One of the main mechanisms is inactivation of β-lactam antibiotics by bacterial β-lactamases. Appearance and spread of these enzymes represent a continuous challenge for the clinical treatment of infections and for the design of new antibiotics and inhibitors. Drug repurposing is a prospective approach for finding new targets for drugs already approved for use. We describe here the inhibitory potency of known detoxifying antidote 2,3-dimercaptopropane-1-sulfonate (unithiol) against metallo-β-lactamases. Unithiol acts as a competitive inhibitor of meropenem hydrolysis by recombinant metallo-β-lactamase NDM-1 with the KI of 16.7 µM. It is an order of magnitude lower than the KI for l-captopril, the inhibitor of angiotensin-converting enzyme approved as a drug for the treatment of hypertension. Phenotypic methods demonstrate that the unithiol inhibits natural metallo-β-lactamases NDM-1 and VIM-2 produced by carbapenem-resistant K. pneumoniae and P. aeruginosa bacterial strains. The 3D full atom structures of unithiol complexes with NDM-1 and VIM-2 are obtained using QM/MM modeling. The thiol group is located between zinc cations of the active site occupying the same place as the catalytic hydroxide anion in the enzyme–substrate complex. The sulfate group forms both a coordination bond with a zinc cation and hydrogen bonds with the positively charged residue, lysine or arginine, responsible for proper orientation of antibiotics upon binding to the active site prior to hydrolysis. Thus, we demonstrate both experimentally and theoretically that the unithiol is a prospective competitive inhibitor of metallo-β-lactamases and it can be utilized in complex therapy together with the known β-lactam antibiotics.
Citations by journals
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Journal of Chemical Information and Modeling
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1 publication, 20%
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Citations by publishers
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1
2
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Royal Society of Chemistry (RSC)
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Royal Society of Chemistry (RSC)
2 publications, 40%
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American Chemical Society (ACS)
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1 publication, 20%
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Multidisciplinary Digital Publishing Institute (MDPI)
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1 publication, 20%
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Taylor & Francis
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Taylor & Francis
1 publication, 20%
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1
2
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Grigorenko V. et al. Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections // International Journal of Molecular Sciences. 2022. Vol. 23. No. 3. p. 1834.
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Grigorenko V., Khrenova M. G., Andreeva I. P., Rubtsova M., Lev A. I., Novikova T. S., Detusheva E. V., Fursova N. K., Dyatlov I. A., Egorov A. M. Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections // International Journal of Molecular Sciences. 2022. Vol. 23. No. 3. p. 1834.
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TY - JOUR
DO - 10.3390/ijms23031834
UR - https://doi.org/10.3390%2Fijms23031834
TI - Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections
T2 - International Journal of Molecular Sciences
AU - Andreeva, Irina P
AU - Lev, Anastasia I
AU - Novikova, Tatiana S.
AU - Detusheva, Elena V
AU - Egorov, Alexey M.
AU - Dyatlov, Ivan A
AU - Grigorenko, V.
AU - Khrenova, Maria G.
AU - Rubtsova, Maya
AU - Fursova, Nadezhda K.
PY - 2022
DA - 2022/02/06 00:00:00
PB - Multidisciplinary Digital Publishing Institute (MDPI)
SP - 1834
IS - 3
VL - 23
PMID - 35163756
SN - 1661-6596
SN - 1422-0067
ER -
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@article{2022_Grigorenko,
author = {Irina P Andreeva and Anastasia I Lev and Tatiana S. Novikova and Elena V Detusheva and Alexey M. Egorov and Ivan A Dyatlov and V. Grigorenko and Maria G. Khrenova and Maya Rubtsova and Nadezhda K. Fursova},
title = {Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections},
journal = {International Journal of Molecular Sciences},
year = {2022},
volume = {23},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
month = {feb},
url = {https://doi.org/10.3390%2Fijms23031834},
number = {3},
pages = {1834},
doi = {10.3390/ijms23031834}
}
Cite this
MLA
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Grigorenko, V., et al. “Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections.” International Journal of Molecular Sciences, vol. 23, no. 3, Feb. 2022, p. 1834. https://doi.org/10.3390%2Fijms23031834.