Tran, Que Tien, Pearlstein, Robert, Williams, Sarah, Reilly, John, Krucker, Thomas and Erdemli, Gul (2014) Structure-kinetic relationship of carbapenem antibacterials permeating through E. coli OmpC porin. Proteins: Structure, Function, and Bioinformatics, 82 (11). pp. 2998-3012. ISSN 1097-0134

Abstract

The emergence of Gram-negative “superbugs” exhibiting resistance to known antibacterials poses a major public health concern. Low molecular weight Gram-negative antibacterials are believed to penetrate the outer bacterial membrane (OM) through porin channels. Therefore, intracellular exposure needed to drive antibacterial target occupancy should depend critically on the translocation rates through these proteins and avoidance of efflux pumps. We used electrophysiology to study the structure-translocation kinetics relationships of a set of carbapenem antibacterials through purified porin OmpC reconstituted in phospholipid bilayers. We also studied the relative susceptibility of OmpC+ and OmpC- E. coli to these compounds as an orthogonal test of translocation. Carbapenems exhibit good efficacy in OmpC-expressing E. coli cells compared to other known antibacterials. Ertapenem, which contains an additional acidic group compared to other analogs, exhibits the fastest entry into OmpC (kon  2x104 M-1s-1). Zwitterionic compounds with highly polar groups attached to the penem-2 ring, including panipenem, imipenem and doripenem exhibit faster kon (>104 M-1s-1), while meropenem and biapenem with fewer exposed polar groups exhibit slower kon (~5x103 M-1s-1). Tebipenem pivoxil and razupenem exhibit ~13-fold slower kon (~1.5x103 M-1s-1) than ertapenem. Overall, our results suggest that a) OmpC serves as an important route of entry of these antibacterials into E. coli cells; and b) that the structure-kinetic relationships of carbapenem translocation are governed by H-bond acceptor/donor composition (in accordance with our previous findings that the enthalpic cost of transferring water from the constriction zone to bulk solvent increases in the presence of exposed non-polar groups).

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/20880