In vivo protein interaction network analysis reveals porin-localized antibiotic inactivation in Acinetobacter baumannii strain AB5075

Xia Wu, Juan D. Chavez, Devin K. Schweppe, Chunxiang Zheng, Chad R. Weisbrod, Jimmy K. Eng, Ananya Murali, Samuel A. Lee, Elizabeth Ramage, Larry A. Gallagher, Hemantha D. Kulasekara, Mauna E. Edrozo, Cassandra N. Kamischke, Mitchell J. Brittnacher, Samuel I. Miller, Pradeep K. Singh, Colin Manoil and James E. Bruce ()
Additional contact information
Xia Wu: University of Washington
Juan D. Chavez: University of Washington
Devin K. Schweppe: University of Washington
Chunxiang Zheng: University of Washington
Chad R. Weisbrod: University of Washington
Jimmy K. Eng: University of Washington
Ananya Murali: University of Washington
Samuel A. Lee: University of Washington
Elizabeth Ramage: University of Washington
Larry A. Gallagher: University of Washington
Hemantha D. Kulasekara: University of Washington
Mauna E. Edrozo: University of Washington
Cassandra N. Kamischke: University of Washington
Mitchell J. Brittnacher: University of Washington
Samuel I. Miller: University of Washington
Pradeep K. Singh: University of Washington
Colin Manoil: University of Washington
James E. Bruce: University of Washington

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract The nosocomial pathogen Acinetobacter baumannii is a frequent cause of hospital-acquired infections worldwide and is a challenge for treatment due to its evolved resistance to antibiotics, including carbapenems. Here, to gain insight on A. baumannii antibiotic resistance mechanisms, we analyse the protein interaction network of a multidrug-resistant A. baumannii clinical strain (AB5075). Using in vivo chemical cross-linking and mass spectrometry, we identify 2,068 non-redundant cross-linked peptide pairs containing 245 intra- and 398 inter-molecular interactions. Outer membrane proteins OmpA and YiaD, and carbapenemase Oxa-23 are hubs of the identified interaction network. Eighteen novel interactors of Oxa-23 are identified. Interactions of Oxa-23 with outer membrane porins OmpA and CarO are verified with co-immunoprecipitation analysis. Furthermore, transposon mutagenesis of oxa-23 or interactors of Oxa-23 demonstrates changes in meropenem or imipenem sensitivity in strain AB5075. These results provide a view of porin-localized antibiotic inactivation and increase understanding of bacterial antibiotic resistance mechanisms.

Date: 2016
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DOI: 10.1038/ncomms13414

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