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Acinetobacter baumannii OmpA Is a Selective Antibiotic Permeant Porin.

Authors
  • Iyer, Ramkumar1
  • Moussa, Samir H1
  • Durand-Réville, Thomas F1
  • Tommasi, Ruben1
  • Miller, Alita1
  • 1 Entasis Therapeutics , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States. , (United States)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Mar 09, 2018
Volume
4
Issue
3
Pages
373–381
Identifiers
DOI: 10.1021/acsinfecdis.7b00168
PMID: 29260856
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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

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