Drug Repurposing of the Unithiol: Inhibition of Metallo-β-Lactamases for the Treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections

被引:8
|
作者
Grigorenko, Vitaly G. [1 ]
Khrenova, Maria G. [1 ,2 ]
Andreeva, Irina P. [1 ]
Rubtsova, Maya Yu. [1 ]
Lev, Anastasia I. [3 ,4 ]
Novikova, Tatiana S. [3 ]
Detusheva, Elena V. [3 ]
Fursova, Nadezhda K. [3 ]
Dyatlov, Ivan A. [3 ]
Egorov, Alexey M. [1 ]
机构
[1] Lomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia
[2] Russian Acad Sci, Fed Res Ctr Fundamentals Biotechnol, Bach Inst Biochem, Moscow 119071, Russia
[3] State Res Ctr Appl Microbiol & Biotechnol, Obolensk 142279, Russia
[4] Weizmann Inst Sci, Feinberg Grad Sch, IL-76100 Rehovot, Israel
基金
俄罗斯科学基金会;
关键词
metallo-beta-lactamase; drug repurposing; antibiotic resistance; molecular modeling; ZINC COORDINATION; NDM-1; INSIGHTS; THIOLS; DMPS;
D O I
10.3390/ijms23031834
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, beta-lactams. One of the main mechanisms is inactivation of beta-lactam antibiotics by bacterial beta-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-beta-lactamases. Unithiol acts as a competitive inhibitor of meropenem hydrolysis by recombinant metallo-beta-lactamase NDM-1 with the K-I of 16.7 mu M. It is an order of magnitude lower than the K-I 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-beta-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-beta-lactamases and it can be utilized in complex therapy together with the known beta-lactam antibiotics.
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页数:16
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