Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections
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. Appearanc...
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MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1834 |
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| author | Vitaly G. Grigorenko Maria G. Khrenova Irina P. Andreeva Maya Yu. Rubtsova Anastasia I. Lev Tatiana S. Novikova Elena V. Detusheva Nadezhda K. Fursova Ivan A. Dyatlov Alexey M. Egorov |
| author_facet | Vitaly G. Grigorenko Maria G. Khrenova Irina P. Andreeva Maya Yu. Rubtsova Anastasia I. Lev Tatiana S. Novikova Elena V. Detusheva Nadezhda K. Fursova Ivan A. Dyatlov Alexey M. Egorov |
| author_sort | Vitaly G. Grigorenko |
| collection | DOAJ |
| description | 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 K<sub>I</sub> of 16.7 µM. It is an order of magnitude lower than the K<sub>I</sub> for <span style="font-variant: small-caps;">l</span>-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 <i>K. pneumoniae</i> and <i>P. aeruginosa</i> 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. |
| first_indexed | 2024-03-09T23:43:41Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:43:41Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4684c64cc4494a87a5a3e0b6ad9b2ef12023-11-23T16:47:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01233183410.3390/ijms23031834Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial InfectionsVitaly G. Grigorenko0Maria G. Khrenova1Irina P. Andreeva2Maya Yu. Rubtsova3Anastasia I. Lev4Tatiana S. Novikova5Elena V. Detusheva6Nadezhda K. Fursova7Ivan A. Dyatlov8Alexey M. Egorov9Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaState Research Center for Applied Microbiology & Biotechnology, 142279 Obolensk, RussiaState Research Center for Applied Microbiology & Biotechnology, 142279 Obolensk, RussiaState Research Center for Applied Microbiology & Biotechnology, 142279 Obolensk, RussiaState Research Center for Applied Microbiology & Biotechnology, 142279 Obolensk, RussiaState Research Center for Applied Microbiology & Biotechnology, 142279 Obolensk, RussiaDepartment of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaThe 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 K<sub>I</sub> of 16.7 µM. It is an order of magnitude lower than the K<sub>I</sub> for <span style="font-variant: small-caps;">l</span>-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 <i>K. pneumoniae</i> and <i>P. aeruginosa</i> 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.https://www.mdpi.com/1422-0067/23/3/1834metallo-β-lactamasedrug repurposingantibiotic resistancemolecular modeling |
| spellingShingle | Vitaly G. Grigorenko Maria G. Khrenova Irina P. Andreeva Maya Yu. Rubtsova Anastasia I. Lev Tatiana S. Novikova Elena V. Detusheva Nadezhda K. Fursova Ivan A. Dyatlov Alexey M. Egorov 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 metallo-β-lactamase drug repurposing antibiotic resistance molecular modeling |
| title | Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections |
| title_full | Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections |
| title_fullStr | Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections |
| title_full_unstemmed | Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections |
| title_short | Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections |
| title_sort | drug repurposing of the unithiol inhibition of metallo β lactamases for the treatment of carbapenem resistant gram negative bacterial infections |
| topic | metallo-β-lactamase drug repurposing antibiotic resistance molecular modeling |
| url | https://www.mdpi.com/1422-0067/23/3/1834 |
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