title: Identification of Acinetobacter baumannii serum-associated antibiotic efflux pump inhibitors.
abstract: Adaptive antibiotic resistance is a newly described phenomenon by which Acinetobacter baumannii induces efflux pump activity in response to host-associated environmental cues that may, in part, account for antibiotic treatment failures against clinically defined susceptible strains. To that end, during adaptation to growth in human serum, the organism induces approximately 22 putative efflux-associated genes and displays efflux-mediated minocycline tolerance at antibiotic concentrations corresponding to patient serum levels. Here, we show that in addition to minocycline, growth in human serum elicits A. baumannii efflux-mediated tolerance to the antibiotics ciprofloxacin, meropenem, tetracycline, and tigecycline. Moreover, using a whole-cell high-throughput screen and secondary assays, we identified novel serum-associated antibiotic efflux inhibitors that potentiated the activities of antibiotics toward serum-grown A. baumannii. Two compounds, Acinetobacter baumannii efflux pump inhibitor 1 (ABEPI1) [(E)-4-((4-chlorobenzylidene)amino)benezenesulfonamide] and ABEPI2 [N-tert-butyl-2-(1-tert-butyltetrazol-5-yl)sulfanylacetamide], were shown to lead to minocycline accumulation within A. baumannii during serum growth and inhibit the efflux potential of the organism. While both compounds also inhibited the antibiotic efflux properties of the bacterial pathogen Pseudomonas aeruginosa, they did not display significant cytotoxicity toward human cells or mammalian Ca(2+) channel inhibitory effects, suggesting that ABEPI1 and ABEPI2 represent promising structural scaffolds for the development of new classes of bacterial antibiotic efflux pump inhibitors that can be used to potentiate the activities of current and future antibiotics for the therapeutic intervention of Gram-negative bacterial infections.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Catlyn
authors.initials: C
authors.lastname: Blanchard
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Barnett
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Jessamyn
authors.initials: J
authors.lastname: Perlmutter
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA paul_dunman@urmc.rochester.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Dunman
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000201:enzymology* / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects*; D015220:Calcium Channels / Q000378:metabolism; D002460:Cell Line; D002939:Ciprofloxacin / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D057809:HEK293 Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D013449:Sulfonamides / Q000494:pharmacology*; D013752:Tetracycline / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology; D000078304:Tigecycline
chemical_list: D000081:Acetamides; C000599911:Acinetobacter baumannii efflux pump inhibitor 1; C000599912:Acinetobacter baumannii efflux pump inhibitor 2; D000900:Anti-Bacterial Agents; D015220:Calcium Channels; D026901:Membrane Transport Proteins; D013449:Sulfonamides; D013777:Tetrazoles; D013845:Thienamycins; D002939:Ciprofloxacin; D000078304:Tigecycline; D013752:Tetracycline; D000077731:Meropenem; D008911:Minocycline
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