Influence of substrates and inhibitors on the structure of Klebsiella pneumoniae carbapenemase-2

Abstract

The hydrolysis of last resort carbapenem antibiotics by Klebsiella pneumoniae carbapenemase-2 (KPC-2) presents a significant danger to global health. Combined with horizontal gene transfer, the emergence KPC-2 threatens to quickly expand carbapenemase activity to ever increasing numbers of pathogens. Our understanding of KPC-2 has greatly increased over the past decade thanks, in great part, to 20 crystal structures solved by groups around the world. These include apo KPC-2 structures, along with structures featuring a library of 10 different inhibitors representing diverse structural and functional classes. Herein we focus on cataloging the available KPC-2 structures and presenting a discussion of key aspects of each structure and important relationships between structures. Although the available structures do not provide information on dynamic motions with KPC-2, and the family of structures indicates small conformational changes across a wide array of bound inhibitors, substrates, and products, the structures provide a strong foundation for additional studies in the coming years to discover new KPC-2 inhibitors.

Impact statement

The work herein is important to the field as it provides a clear and succinct accounting of available KPC-2 structures. The work advances the field by collecting and analyzing differences and similarities across the available structures. This work features new analyses and interpretations of the existing structures which will impact the field in a positive way by making structural insights more widely available among the beta-lactamase community.