Membrane Distribution of the
            <i>Pseudomonas</i>
            Quinolone Signal Modulates Outer Membrane Vesicle Production in
            <i>Pseudomonas aeruginosa</i>

Florez, Catalina; Raab, Julie E.; Cooke, Adam C.; Schertzer, Jeffrey W.

doi:10.1128/mbio.01034-17

Cited by 99 publications

(118 citation statements)

References 59 publications

(74 reference statements)

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“…This long-range stress response complements the short-range kin lysis stress system previously reported in P. aeruginosa (54). PQS activates heightened stress responses in P. aeruginosa, including the formation of outer membrane vesicles, which interfere with cytokine production and deliver toxins to target host cells (55)(56)(57). Through activation of the PqsR receptor, PQS also induces pqsE expression, which synthesizes a QS molecule that activates RhlR and is thereby responsible for regulation of key virulence factors that kill plants and animals, including hydrogen cyanide and elastase (41,58,59).…”

Section: Discussionsupporting

confidence: 69%

PQS Produced by the Pseudomonas aeruginosa Stress Response Repels Swarms Away from Bacteriophage and Antibiotics

et al. 2019

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We investigate the effect of bacteriophage infection and antibiotic treatment on the coordination of swarming, a collective form of flagellum-and pilus-mediated motility in bacteria. We show that phage infection of the opportunistic bacterial pathogen Pseudomonas aeruginosa abolishes swarming motility in the infected subpopulation and induces the release of the Pseudomonas quinolone signaling molecule PQS, which repulses uninfected subpopulations from approaching the infected area. These mechanisms have the overall effect of limiting the infection to a subpopulation, which promotes the survival of the overall population. Antibiotic treatment of P. aeruginosa elicits the same response, abolishing swarming motility and repulsing approaching swarms away from the antibiotic-treated area through a PQS-dependent mechanism. Swarms are entirely repelled from the zone of antibiotic-treated P. aeruginosa, consistent with a form of antibiotic evasion, and are not repelled by antibiotics alone. PQS has multiple functions, including serving as a quorum-sensing molecule, activating an oxidative stress response, and regulating the release of virulence and host-modifying factors. We show that PQS serves additionally as a stress warning signal that causes the greater population to physically avoid cell stress. The stress response at the collective level observed here in P. aeruginosa is consistent with a mechanism that promotes the survival of bacterial populations. IMPORTANCE We uncover a phage-and antibiotic-induced stress response in the clinically important opportunistic pathogen Pseudomonas aeruginosa. Phage-infected P. aeruginosa subpopulations are isolated from uninfected subpopulations by the production of a stress-induced signal. Activation of the stress response by antibiotics causes P. aeruginosa to physically be repelled from the area containing antibiotics altogether, consistent with a mechanism of antibiotic evasion. The stress response observed here could increase P. aeruginosa resilience against antibiotic treatment and phage therapy in health care settings, as well as provide a simple evolutionary strategy to avoid areas containing stress.

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Section: Discussionsupporting

confidence: 69%

PQS Produced by the Pseudomonas aeruginosa Stress Response Repels Swarms Away from Bacteriophage and Antibiotics

et al. 2019

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“…In P. aeruginosa, the PQS molecule and associated regulatory pathway are linked to numerous cellular processes including swarm repression, stress response, cell lysis, DNA release, outer membrane vesicles (OMV) biogenesis, and biofilm development (20)(21)(22)24,29,45). The AQNOs, HQNO and NQNO, are both effective antiStaphylococcal molecules that modulate the interaction between P. aeruginosa and Staphylococcus aureus (18,25).…”

Section: Discussionmentioning

confidence: 99%

“…In the Pseudomonas literature, AQs are generally presented to contain 7-Carbon (C7) side chains (HHQ, PQS, and HQNO), yet 9-Carbon (C9; NHQ, C9-PQS, and NQNO) and 11-Carbon (C11; UHQ, C11-PQS, and UQNO) side chain variants of these molecules are also common (16,17). The extracellular presence of PQS in P. aeruginosa communities is attributed to packaging and transport in outer membrane vesicles (OMVs) (28,29), yet cell lysis could also contribute to their release (30).…”

Section: Introductionmentioning

confidence: 99%

Spatially dependent alkyl quinolone signaling responses to antibiotics in Pseudomonas aeruginosa swarms

Morales-Soto¹,

Dunham

Baig

et al. 2018

Journal of Biological Chemistry

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There is a general lack of understanding about how communities of bacteria respond to exogenous toxins such as antibiotics. Most of our understanding of community-level stress responses comes from the study of stationary biofilm communities. Although several community behaviors and production of specific biomolecules affecting biofilm development and associated behavior have been described for Pseudomonas aeruginosa and other bacteria, we have little appreciation for the production and dispersal of secreted metabolites within the 2D and 3D spaces they occupy as they colonize, spread, and grow on surfaces. Here we specifically studied the phenotypic responses and spatial variability of alkyl quinolones, including the Pseudomonas quinolone signal (PQS) and members of the alkyl hydroxyquinoline (AQNO) subclass, in P. aeruginosa plateassay swarming communities. We found that PQS production was not a universal signaling response to antibiotics as tobramycin elicited an alkyl quinolone response while carbenicillin did not. We also found that PQS and AQNO profiles in response to tobramycin were markedly distinct and influenced these swarms on different spatial scales. The distribution of alkyl quinolones varied by several orders of magnitude within the same swarm. At some tobramycin exposures, P. aeruginosa swarms produced alkyl quinolones in the range of 150 µM PQS and 400 µM AQNO that accumulated as aggregates.

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“…The overall amphiphilicity of PQS and its task-specific functional groups enable a strong association with LPS in the outer leaflet (13). The insertion of PQS into the membrane leads to an asymmetric expansion of the outer leaflet compared with the inner leaflet, which drives the induction of membrane curvature and subsequent pinch-off of the OMV (11,14). Recent experiments have shown that other gammaproteobacteria also respond to PQS by increasing OMV formation, which suggests that small molecule-induced OMV biogenesis is a general mechanism that is driven by biophysical interactions with target membranes (15).…”

mentioning

confidence: 99%

Molecular conformation affects the interaction of the Pseudomonas quinolone signal with the bacterial outer membrane

Schertzer

Yong

2019

Journal of Biological Chemistry

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Gram-negative bacteria produce outer-membrane vesicles (OMVs) that package genetic elements, virulence factors, and cell-to-cell communication signaling compounds. Despite their importance in many disease-related processes, how these versatile structures are formed is incompletely understood. A selfproduced secreted small molecule, the Pseudomonas quinolone signal (PQS), has been shown to initiate OMV formation in Pseudomonas aeruginosa by interacting with the outer membrane (OM) and inducing its curvature. Other bacterial species have also been shown to respond to PQS, supporting a common biophysical mechanism. Here, we conducted molecular dynamics simulations to elucidate the specific interactions between PQS and a model P. aeruginosa OM at the atomistic scale. We discovered two characteristic states of PQS interacting with the biologically relevant membrane, namely attachment to the membrane surface and insertion into the lipid A leaflet. The hydrogen bonds between PQS and the lipid A phosphates drove the PQSmembrane association. An analysis of PQS trajectory and molecular conformation revealed sequential events critical for spontaneous insertion, including probing, docking, folding, and insertion. Remarkably, PQS bent its hydrophobic side chain into a closed conformation to lower the energy barrier for penetration through the hydrophilic headgroup zone of the lipid A leaflet, which was confirmed by the potential of mean force (PMF) measurements. Attachment and insertion were simultaneously observed in the simulation with multiple PQS molecules. Our findings uncover a sequence of molecular interactions that drive PQS insertion into the bacterial OM and provide important insight into the biophysical mechanism of small molecule-induced OMV biogenesis.Outer-membrane vesicles (OMVs) 2 derived from the bacterial outer membrane (OM) are instrumental in bacterial interactions.They are spherical membranous structures that can package cargoes, such as virulence factors, proteins, DNA, RNA, and signaling molecules (1-3). In contrast to the well-known functions of OMVs in trafficking systems, the biogenesis of OMVs is still under investigation. Several mechanisms for OMV formation have been proposed (3, 4). One hypothesis builds on the accumulation of chemical compounds (e.g. misfolded proteins (5) or muramyl peptides (6)) in the periplasmic space. These fragments create turgor pressure on the OM and further stimulate vesicle formation. Another proposed mechanism focuses on reduced cross-linking between the OM and peptidoglycan layer. The lack of trans-envelope proteins untethers the OM from the cell wall (7, 8), and vesiculation occurs when the OM grows faster than the peptidoglycan layer (9). Emphasizing the membrane surface, a third explanation highlights the intercalation of molecules, such as antibiotics, phospholipids, and signaling molecules, into the outer leaflet of OM (4, 10, 11). Li et al. (10) discussed that the presence of cationic antibiotics destabilizes the OM by collapsing salt bridges between lipopolysa...

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Membrane Distribution of the Pseudomonas Quinolone Signal Modulates Outer Membrane Vesicle Production in Pseudomonas aeruginosa

Cited by 99 publications

References 59 publications

PQS Produced by the Pseudomonas aeruginosa Stress Response Repels Swarms Away from Bacteriophage and Antibiotics

PQS Produced by the Pseudomonas aeruginosa Stress Response Repels Swarms Away from Bacteriophage and Antibiotics

Spatially dependent alkyl quinolone signaling responses to antibiotics in Pseudomonas aeruginosa swarms

Molecular conformation affects the interaction of the Pseudomonas quinolone signal with the bacterial outer membrane

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