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Abstract
Carbapenem resistance caused by metallo-β-lactamases is a serious global challenge that, if not tackled efficiently, is expected to lead to millions of deaths in the coming decades. Verona-integron encoded metallo-β-lactamase 2 (VIM-2) is a bacterial enzyme that has been reported from multidrug-resistant nosocomial isolates of Pseudomonas aeruginosa and other Gram-negative pathogens. As it hydrolyzes most β-lactams efficiently, including carbapenems, it is a major threat to current antimicrobial chemotherapies. So far, there is no clinically applicable inhibitor for this enzyme. In this work, the backbone NMR resonance assignment of VIM-2 is disclosed, opening up NMR investigations of this clinically important enzyme and its potential inhibitors for solutions, enabling a rational improvement of inhibitor candidates. Making use of the assignment, we identified the active enantiomer of a VIM-2 inhibitor candidate as well as its possible binding site and Kd, utilizing NMR chemical shift titration experiments.
Highlights
Carbapenem resistance caused by metallo-β-lactamases is a serious global challenge that, if not tackled efficiently, is expected to lead to millions of deaths in the coming decades
Bacteria have developed an arsenal of resistance mechanisms, of which metallo-β-lactamases are among the most devastating. These enzymes dismantle β-lactams, the cheapest and most widely used group of antibiotics, and deactivate carbapenems, our lastresort antibiotics that are reserved for the treatment of multidrug resistant infections.[5]
Inhibiting metallo-β-lactamase activity is expected to provide a potential solution for the emerging crisis by allowing a renewed use of broad-spectrum β-lactam antibiotics, such as penicillins, cephalosporins, and carbapenems.[5−8] Metallo-βlactamases have been divided into three (Ambler) subcategories: B1, B2, and B3.6−9 Subclass B1 is the most prevalent among clinically relevant strains, with the New Delhi metalloβ-lactamases (NDMs), Verona-integron encoded metallo-βlactamases (VIMs), imipenemases (IMPs), and German imipenemases (GIMs) belonging to this subclass and the common structural element being two zinc residues in their active site.[6]
Summary
Carbapenem resistance caused by metallo-β-lactamases is a serious global challenge that, if not tackled efficiently, is expected to lead to millions of deaths in the coming decades. We report the first NMR backbone assignment (Figure 1) of VIM-2 as well as that of its complex with Lcaptopril, a previously identified binder (IC50 4.4 μM).[14] We further identify the active enantiomer of 1 (Figure 2), a Scheme 1.
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