Acinetobacter baumannii OmpA Is a Selective Antibiotic Permeant Porin.

Abstract

OmpAis a conserved, abundantly expressed outer membrane porin in Acinetobacter baumannii whose presumed role in antibiotic permeation has not been clearly demonstrated. In this report, we use a titratable heterologous expression system to express OmpAin isolation and demonstrate selective passage of small molecule antibiotics through OmpA. ETX2514, a recently discovered broad-spectrum β-lactamase inhibitor, in combination with sulbactam, is currently in clinical testing for the treatment of drug-resistant A. baumannii infections. We demonstrate that ETX2514 permeates OmpAand potentiates the activity of sulbactam in an OmpA-dependent manner. In addition, we show that small modifications in the structure of ETX2514 differentially affect its passage through OmpA, revealing unique structure-porin-permeation relationships. Finally, we confirm the contribution of OmpAto bacterial fitness using a murine thigh model of A. baumannii infection. These results, combined with the high sequence homology of OmpA across Acinetobacter spp., suggest that optimization of antibiotic entry through OmpAmay prove to be a feasible medicinal chemistry design strategy for future antibacterial discovery efforts.