Two Regulators, PA3898 and PA2100, Modulate the Pseudomonas aeruginosa Multidrug Resistance MexAB-OprM and EmrAB Efflux Pumps and Biofilm Formation
It is generally believed that the Pseudomonas aeruginosa biofilm matrix itself acts as a molecular sieve or sink that contributes to significant levels of drug resistance, but it is becoming more apparent that multidrug efflux pumps induced during biofilm growth significantly enhance resistance leve...
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Veröffentlicht in: | Antimicrobial agents and chemotherapy 2018-11, Vol.62 (12) |
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Sprache: | eng |
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Zusammenfassung: | It is generally believed that the
Pseudomonas aeruginosa
biofilm matrix itself acts as a molecular sieve or sink that contributes to significant levels of drug resistance, but it is becoming more apparent that multidrug efflux pumps induced during biofilm growth significantly enhance resistance levels. We present here a novel transcriptional regulator, PA3898, which controls biofilm formation and multidrug efflux pumps in
P. aeruginosa
.
It is generally believed that the
Pseudomonas aeruginosa
biofilm matrix itself acts as a molecular sieve or sink that contributes to significant levels of drug resistance, but it is becoming more apparent that multidrug efflux pumps induced during biofilm growth significantly enhance resistance levels. We present here a novel transcriptional regulator, PA3898, which controls biofilm formation and multidrug efflux pumps in
P. aeruginosa
. A mutant of this regulator significantly reduced the ability of
P. aeruginosa
to produce biofilm
in vitro
and affected its
in vivo
fitness and pathogenesis in
Drosophila melanogaster
and BALB/c mouse lung infection models. Transcriptome analysis revealed that PA3898 modulates essential virulence genes/pathways, including multidrug efflux pumps and phenazine biosynthesis. Chromatin immunoprecipitation sequencing (ChIP-seq) identified its DNA binding sequences and confirmed that PA3898 directly interacts with promoter regions of four genes/operons, two of which are
mexAB-oprM
and
phz2
. Coimmunoprecipitation revealed a regulatory partner of PA3898 as PA2100, and both are required for binding to DNA in electrophoretic mobility shift assays. PA3898 and PA2100 were given the names MdrR1 and MdrR2, respectively, as novel repressors of the
mexAB-oprM
multidrug efflux operon and activators for another multidrug efflux pump, EmrAB. The interaction between MdrR1 and MdrR2 at the promoter regions of their regulons was further characterized via localized surface plasmon resonance and DNA footprinting. These regulators directly repress the
mexAB-oprM
operon, independent of its well-established MexR regulator. Mutants of
mdrR1
and
mdrR2
caused increased resistance to multiple antibiotics in
P. aeruginosa
, validating the significance of these newly discovered regulators. |
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ISSN: | 0066-4804 1098-6596 |
DOI: | 10.1128/AAC.01459-18 |