182750-64-7Relevant academic research and scientific papers
Crystal structures of KPC-2 β-lactamase in complex with 3-nitrophenyl boronic acid and the penam sulfone PSR-3-226
Ke, Wei,Bethel, Christopher R.,Papp-Wallace, Krisztina M.,Pagadala, Sundar Ram Reddy,Nottingham, Micheal,Fernandez, Daniel,Buynak, John D.,Bonomo, Robert A.,Van Den Akker, Focco
, p. 2713 - 2718 (2012/08/27)
Class A carbapenemases are a major threat to the potency of carbapenem antibiotics. A widespread carbapenemase, KPC-2, is not easily inhibited by β-lactamase inhibitors (i.e., clavulanic acid, sulbactam, and tazobactam). To explore different mechanisms of inhibition of KPC-2, we determined the crystal structures of KPC-2 with two β-lactamase inhibitors that follow different inactivation pathways and kinetics. The first complex is that of a small boronic acid compound, 3-nitrophenyl boronic acid (3-NPBA), bound to KPC-2 with 1.62-A resolution. 3-NPBA demonstrated a Km value of 1.0±0.1 μM (mean±standard error) for KPC-2 and blocks the active site by making a reversible covalent interaction with the catalytic S70 residue. The two boron hydroxyl atoms of 3-NPBA are positioned in the oxyanion hole and the deacylation water pocket, respectively. In addition, the aromatic ring of 3-NPBA provides an edge-to-face interaction with W105 in the active site. The structure of KPC-2 with the penam sulfone PSR-3-226 was determined at 1.26-A resolution. PSR-3-226 displayed a Km value of 3.8±0.4 μM for KPC-2, and the inactivation rate constant (k inact) was 0.034±0.003 s-1. When covalently bound to S70, PSR-3-226 forms a trans-enamine intermediate in the KPC-2 active site. The predominant active site interactions are generated via the carbonyl oxygen, which resides in the oxyanion hole, and the carboxyl moiety of PSR-3-226, which interacts with N132, N170, and E166. 3-NPBA and PSR-3-226 are the first β-lactamase inhibitors to be trapped as an acyl-enzyme complex with KPC-2. The structural and inhibitory insights gained here could aid in the design of potent KPC-2 inhibitors. Copyright
Synthesis and biological evaluation of penam sulfones as inhibitors of β-lactamases
Phillips, Oludotun A.,Reddy, Andhe V.N.,Setti, Eduardo L.,Spevak, Paul,Czajkowski, David P.,Atwal, Herninder,Salama, Sameeh,Micetich, Ronald G.,Maiti, Samarendra N.
, p. 2847 - 2858 (2007/10/03)
The chemical synthesis of a series of new penam sulfone derivatives bearing a 2β-substituted-oxyimino and -hydrazone substituents, their β-lactamase inhibitory properties against selected enzymes representing class A and C β-lactamases are reported. The o
