Project 1 will identify and assign functions to conserved genes of unknown function in Acinetobacter baumannii, an emerging pathogen that causes hospital-acquired, antibiotic resistant infections. The project will focus on protein-coding genes that contribute to any of seven clinically relevant resistance traits. We hypothesize that such genes control the expression and activities of efflux pumps, membrane permeability determinants, inactivating enzymes, and stress responses. Genes required for resistance to four antibiotics, two biocides and desiccation will first be identified by genome-scale mutant screening using Tn-seq technology. A subset of the resistance genes of unknown function will then be characterized using a battery of genetic, genomic and proteomic approaches. The results will be interpreted in the context of current understanding of each trait in order to formulate potential molecular functions for the genes examined. Hypothesized functions will then be tested using approaches tailored to individual genes.

Public Health Relevance

Acinetobacter baumannii has emerged in recent decades as an important agent of hospital-acquired infections throughout the worid. The pathogen's emergence can be understood in large part by its high resistance to antibiotics, biocides and desiccation. The proposed studies will identify the gene functions responsible for several such resistance traits. The work should identify targets for drugs to enhance the efficacy of established antibiotics in treating Ab infections and for agents that decrease environmental persistence of the bacterium.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-FDS-M)
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University of Washington
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Schweppe, Devin K; Chavez, Juan D; Lee, Chi Fung et al. (2017) Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry. Proc Natl Acad Sci U S A 114:1732-1737
Zhong, Xuefei; Navare, Arti T; Chavez, Juan D et al. (2017) Large-Scale and Targeted Quantitative Cross-Linking MS Using Isotope-Labeled Protein Interaction Reporter (PIR) Cross-Linkers. J Proteome Res 16:720-727
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Schweppe, Devin K; Chavez, Juan D; Bruce, James E (2016) XLmap: an R package to visualize and score protein structure models based on sites of protein cross-linking. Bioinformatics 32:306-8
Chavez, Juan D; Eng, Jimmy K; Schweppe, Devin K et al. (2016) A General Method for Targeted Quantitative Cross-Linking Mass Spectrometry. PLoS One 11:e0167547
Schweppe, Devin K; Zheng, Chunxiang; Chavez, Juan D et al. (2016) XLinkDB 2.0: integrated, large-scale structural analysis of protein crosslinking data. Bioinformatics 32:2716-8

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