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Crystal structure of KPC-2 beta-lactamase in complex with the S02030 boronic acid inhibitorCrystal structure of KPC-2 beta-lactamase in complex with the S02030 boronic acid inhibitor
Structural highlights
FunctionBLKPC_KLEPN Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. Publication Abstract from PubMedResistance to expanded-spectrum cephalosporins and carbapenems has rendered certain strains of Klebsiella pneumoniae as the most problematic pathogens infecting patients in the hospital and community. This broad spectrum resistance to beta-lactamas emerges in part via the expression of KPC-2 and SHV-1 beta-lactamases, and variants thereof, KPC-2 carbapenemase is particularly worrisome as the genetic determinant encoding this beta-lactamase is rapidly spread via plasmids. Moreover, KPC-2, a class A enzyme, is difficult to inhibit with mechanism based inactivators (i.e. clavulanate). In order to develop new beta-lactamase inhibitors (BLIs) to add to the limited available armamentarium that can inhibit KPC-2, we have structurally probed the boronic acid transition state analog S02030 for its inhibition of KPC-2 and SHV-1. S02030 contains a boronic acid, a thiophene, and a carboxyl triazole moiety. We present here the 1.54 and 1.87 A resolution crystal structures of S02030 bound to SHV-1 and KPC-2 beta-lactamases, respectively, as well as a comparative analysis of the S02030 binding modes including a previously determined S02030 Class C ADC-7 beta-lactamase complex. Upon analysis, S02030 is able to inhibit vastly different serine beta-lactamases by interacting with the conserved features of these actives sites which includes i) forming the bond with catalytic serine via the boron atom; ii) positioning of one of the boronic acid oxygens in the oxyanion hole; and iii) utilizing its amide moiety to make conserved interactions across the width of the active site. In addition, S02030 is able to overcome more distantly located structural differences between the beta-lactamases. This unique feature is achieved by re-positionig the more polar carboxyl-triazole moiety, generated by click chemistry, to create polar interactions as well as reorient the more hydrophobic thiophene moiety. The former is aided by the unusual polar nature of the triazole ring allowing it to potentially form a unique C-H ...O 2.9A hydrogen bond with S130 in KPC-2. Crystal structures of KPC-2 and SHV-1 beta-lactamases in complex with the boronic acid transition state analog S02030.,Nguyen NQ, Krishnan NP, Rojas LJ, Prati F, Caselli E, Romagnoli C, Bonomo RA, van den Akker F Antimicrob Agents Chemother. 2016 Jan 4. pii: AAC.02643-15. PMID:26729491[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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