PMID- 25114126
OWN - NLM
STAT- MEDLINE
DCOM- 20150803
LR  - 20211021
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 58
IP  - 11
DP  - 2014 Nov
TI  - Identification of Acinetobacter baumannii serum-associated antibiotic efflux pump 
      inhibitors.
PG  - 6360-70
LID - 10.1128/AAC.03535-14 [doi]
AB  - 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.
CI  - Copyright (c) 2014, American Society for Microbiology. All Rights Reserved.
FAU - Blanchard, Catlyn
AU  - Blanchard C
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
FAU - Barnett, Pamela
AU  - Barnett P
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
FAU - Perlmutter, Jessamyn
AU  - Perlmutter J
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
FAU - Dunman, Paul M
AU  - Dunman PM
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA paul_dunman@urmc.rochester.edu.
LA  - eng
GR  - R01 AI103507/AI/NIAID NIH HHS/United States
GR  - T90 DE021985/DE/NIDCR NIH HHS/United States
GR  - R01AI103507/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140811
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Acetamides)
RN  - 0 (Acinetobacter baumannii efflux pump inhibitor 1)
RN  - 0 (Acinetobacter baumannii efflux pump inhibitor 2)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Calcium Channels)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Sulfonamides)
RN  - 0 (Tetrazoles)
RN  - 0 (Thienamycins)
RN  - 5E8K9I0O4U (Ciprofloxacin)
RN  - 70JE2N95KR (Tigecycline)
RN  - F8VB5M810T (Tetracycline)
RN  - FV9J3JU8B1 (Meropenem)
RN  - FYY3R43WGO (Minocycline)
SB  - IM
MH  - Acetamides/*pharmacology
MH  - Acinetobacter Infections/drug therapy/microbiology
MH  - Acinetobacter baumannii/drug effects/*enzymology/isolation & purification
MH  - Anti-Bacterial Agents/adverse effects/blood/pharmacology
MH  - Biological Transport/*drug effects
MH  - Calcium Channels/metabolism
MH  - Cell Line
MH  - Ciprofloxacin/pharmacology
MH  - Drug Resistance, Multiple, Bacterial
MH  - HEK293 Cells
MH  - Humans
MH  - Membrane Transport Proteins/*metabolism
MH  - Meropenem
MH  - Microbial Sensitivity Tests
MH  - Minocycline/analogs & derivatives/blood/pharmacology
MH  - Pseudomonas aeruginosa/drug effects/enzymology
MH  - Sulfonamides/*pharmacology
MH  - Tetracycline/pharmacology
MH  - Tetrazoles/*pharmacology
MH  - Thienamycins/pharmacology
MH  - Tigecycline
PMC - PMC4249429
EDAT- 2014/08/13 06:00
MHDA- 2015/08/04 06:00
PMCR- 2015/05/01
CRDT- 2014/08/13 06:00
PHST- 2014/08/13 06:00 [entrez]
PHST- 2014/08/13 06:00 [pubmed]
PHST- 2015/08/04 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - AAC.03535-14 [pii]
AID - 03535-14 [pii]
AID - 10.1128/AAC.03535-14 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2014 Nov;58(11):6360-70. doi: 10.1128/AAC.03535-14. 
      Epub 2014 Aug 11.