2019
DOI: 10.1128/aac.01313-19
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Potentiation of Aminoglycoside Lethality by C 4 -Dicarboxylates Requires RpoN in Antibiotic-Tolerant Pseudomonas aeruginosa

Abstract: Antibiotic tolerance contributes to the inability of standard antimicrobial therapies to clear the chronic Pseudomonas aeruginosa lung infections that often afflict patients with cystic fibrosis (CF). Metabolic potentiation of bactericidal antibiotics with carbon sources has emerged as a promising strategy to resensitize tolerant bacteria to antibiotic killing. Fumarate (FUM), a C4-dicarboxylate, has been recently shown to resensitize tolerant P. aeruginosa to killing by tobramycin (TOB), an aminoglycoside ant… Show more

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Cited by 12 publications
(9 citation statements)
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“…The exact mechanism underlying the bactericidal activity of aminoglycosides has been subject of debate in the literature [ 37 ] but it is generally accepted that killing by AGs involves i) the uptake of the AG into the cytoplasm [ 11 , 38 , 39 ] and ii) membrane disruption mediated by insertion of misfolded proteins in the membrane as consequence of AG binding to the ribosomes and disruption of translational fidelity [ 11 13 , 40 ]. Indeed, mechanisms modulating aminoglycoside tolerance/resistance in different bacterial species (in exponential or stationary phase) have been shown to be associated either to AG uptake [ 41 44 ] or to translational fidelity and proteostasis [ 14 , 29 , 40 , 45 ]. Our results revealed a higher relative abundance of groESL-2 transcripts in bacterial cells lacking VchM, which led us to hypothesize that such increased expression of these chaperonins could underlie the high tolerance to AGs observed in this mutant, as it had been previously observed in E .…”
Section: Discussionmentioning
confidence: 99%
“…The exact mechanism underlying the bactericidal activity of aminoglycosides has been subject of debate in the literature [ 37 ] but it is generally accepted that killing by AGs involves i) the uptake of the AG into the cytoplasm [ 11 , 38 , 39 ] and ii) membrane disruption mediated by insertion of misfolded proteins in the membrane as consequence of AG binding to the ribosomes and disruption of translational fidelity [ 11 13 , 40 ]. Indeed, mechanisms modulating aminoglycoside tolerance/resistance in different bacterial species (in exponential or stationary phase) have been shown to be associated either to AG uptake [ 41 44 ] or to translational fidelity and proteostasis [ 14 , 29 , 40 , 45 ]. Our results revealed a higher relative abundance of groESL-2 transcripts in bacterial cells lacking VchM, which led us to hypothesize that such increased expression of these chaperonins could underlie the high tolerance to AGs observed in this mutant, as it had been previously observed in E .…”
Section: Discussionmentioning
confidence: 99%
“…These nitrogen sources include nitrate, which is abundant in the lungs of CF patients (up to 400 μM; Line et al., 2014 ), as well as glutamate, which is also abundant in CF sputum ( Palmer et al., 2005 ) and several other anatomical niches. Similarly, antibiotic susceptibility is dependent on central metabolism and can be potentiated or inhibited by addition of dicarboxylates such as fumarate or glyoxylate, respectively ( Meylan et al., 2017 ; Hall et al., 2019 ). Tight regulation of gene expression through two-component system signaling allows P. aeruginosa to rapidly respond to environmental heterogeneity, contributing to its adaptability ( Kollaran et al., 2019 ).…”
Section: Introductionmentioning
confidence: 99%
“…The exact mechanism underlying the bactericidal activity of aminoglycosides has been subject of debate in the literature (37) but it is generally accepted that killing by AGs involves i) the uptake of the AG into the cytoplasm (11,38,39) and ii) membrane disruption mediated by insertion of misfolded proteins in the membrane as consequence of AG binding to the ribosomes and disruption of translational fidelity (11)(12)(13)40). Indeed, mechanisms modulating aminoglycoside tolerance/resistance in different bacterial species (in exponential or stationary phase) have been shown to be associated either to AG uptake (41)(42)(43)(44) or to translational fidelity and proteostasis (14,29,40,45). Our results revealed a higher relative abundance of groESL-2 transcripts in bacterial cells lacking VchM, which led us to hypothesize that such increased expression of these chaperonins could underlie the high tolerance to AGs observed in this mutant, as it had been previously observed in E. coli (29).…”
Section: Discussionmentioning
confidence: 99%