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.
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.
|Karalewitz, Andrew P-A; Miller, Samuel I (2018) Multidrug-Resistant Acinetobacter baumannii Chloramphenicol Resistance Requires an Inner Membrane Permease. Antimicrob Agents Chemother 62:|
|Chavez, Juan D; Lee, Chi Fung; Caudal, Arianne et al. (2018) Chemical Crosslinking Mass Spectrometry Analysis of Protein Conformations and Supercomplexes in Heart Tissue. Cell Syst 6:136-141.e5|
|Vreven, Thom; Schweppe, Devin K; Chavez, Juan D et al. (2018) Integrating Cross-Linking Experiments with Ab Initio Protein-Protein Docking. J Mol Biol 430:1814-1828|
|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|
|Gallagher, Larry A; Lee, Samuel A; Manoil, Colin (2017) Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait. MBio 8:|
|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|
|Miller, Samuel I (2016) Antibiotic Resistance and Regulation of the Gram-Negative Bacterial Outer Membrane Barrier by Host Innate Immune Molecules. MBio 7:|
|Baric, Ralph S; Crosson, Sean; Damania, Blossom et al. (2016) Next-Generation High-Throughput Functional Annotation of Microbial Genomes. MBio 7:|
|Chavez, Juan D; Schweppe, Devin K; Eng, Jimmy K et al. (2016) In Vivo Conformational Dynamics of Hsp90 and Its Interactors. Cell Chem Biol 23:716-26|
|Schweppe, Devin K; Chavez, Juan D; Navare, Arti T et al. (2016) Spectral Library Searching To Identify Cross-Linked Peptides. J Proteome Res 15:1725-31|
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