Acinetobacter baumannii OmpA Is a Selective Antibiotic Permeant Porin

OmpA_Ab is 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 OmpA_Ab in isolation and demonstrate selective passage of small molecule antibiotics through OmpA_Ab. 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 OmpA_Ab and potentiates the activity of sulbactam in an OmpA_Ab-dependent manner. In addition, we show that small modifications in the structure of ETX2514 differentially affect its passage through OmpA_Ab, revealing unique structure-porin-permeation relationships. Finally, we confirm the contribution of OmpA_Ab to 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 OmpA_Ab may prove to be a feasible medicinal chemistry design strategy for future antibacterial discovery efforts.