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.
Highlights
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
Significant efforts have already been invested to better understand multidrug resistance mechanisms in A. baumannii. These results revealed that b-lactamases and membrane porins are major genetic determinants of A. baumannii drug resistance3,9. b-Lactamase enzymes represent a class of unique transpeptidases that possess hydrolytic activity against b-lactam antibiotics
1,148 cross-links correspond to 245 intramolecular interactions and the remaining 920 cross-links represent 398 inter-molecular interactions
Summary
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. 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. Significant efforts have already been invested to better understand multidrug resistance mechanisms in A. baumannii These results revealed that b-lactamases and membrane porins are major genetic determinants of A. baumannii drug resistance. One reason may be that oxa-23 and carO genes have genetic interactions when both are present Another reason could be that additional factors that are not yet identified contribute to drug resistance in AB5075. We decided to investigate the protein interaction network in AB5075 cells, first to identify protein interactions for protein candidates that are known to be important for antibiotic resistance (including Oxa-23 and CarO) and, second, to identify novel protein targets that may be associated with antibiotic resistance in AB5075 cells based on the protein interaction data
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