Efflux Pumps

Poole, Keith

doi:10.1007/978-1-4419-9086-0_21

Cited by 29 publications

(21 citation statements)

References 238 publications

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“…3B, lane 4), exactly mirroring the antibiotic and PA5471 dependence of mexXY expression. This is consistent with mexZ being subject to autoregulation, as for repressors of other multidrug efflux systems (41,44), and given the low levels of mexZ mRNA detected (it took a minimum of 40 cycles to detect mexZ using RT-PCR), it is not inconsistent with antibiotics and/or PA5471 positively impacting mexXY expression via modulation of MexZ repressor activity.…”

Section: Resultssupporting

confidence: 73%

“…Pseudomonas aeruginosa expresses several three-component RND-type multidrug efflux systems, among which four, MexABOprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM, are reported to be significant determinants of multidrug resistance in lab and clinical isolates (41,44). A clear indication, however, that antimicrobial export may not be the intended function of many of these systems comes from the observation that while these pumps accommodate many of the same antimicrobials, each appears to be independently regulated by linked regulatory genes (44), but not (with the exception of MexXY [30]) in response to antibiotics.…”

mentioning

confidence: 99%

“…A clear indication, however, that antimicrobial export may not be the intended function of many of these systems comes from the observation that while these pumps accommodate many of the same antimicrobials, each appears to be independently regulated by linked regulatory genes (44), but not (with the exception of MexXY [30]) in response to antibiotics.…”

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confidence: 99%

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Antibiotic Inducibility of the MexXY Multidrug Efflux System of Pseudomonas aeruginosa : Involvement of the Antibiotic-Inducible PA5471 Gene Product

2006

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The MexXY components of the MexXY-OprM multidrug efflux system of Pseudomonas aeruginosa are encoded by a MexZ repressor-regulated operon that is inducible by antibiotics that target the ribosome. Mutant strains disrupted in a gene, PA5471, were shown to be compromised for drug-inducible mexXY expression and, therefore, MexXY-OprM-mediated antimicrobial resistance. The PA5471 gene was inducible by the same ribosometargeting agents that induce mexXY expression. Moreover, vector-driven expression of cloned PA5471 was sufficient to promote mexXY expression and MexXY-mediated resistance in the absence of antibiotic exposure, consistent with PA5471 directly or indirectly activating mexXY expression following its own upregulation in response to antibiotics. The requirement for PA5471 for mexXY expression and antimicrobial resistance was, however, obviated in mutants lacking the MexZ repressor of mexXY expression, suggesting that PA5471 directly or indirectly modulates MexZ activity in effecting mexXY expression. While the recruitment of PA5471 and MexXY in response to ribosome disruption by antimicrobials is consistent with their genes playing a role in protecting cells from the adverse consequences of disrupting the translation process, reminiscent of transtranslation, these genes appear to operate independently in their contribution to resistance: mutants defective in trans-translation showed a much more modest (twofold) decrease in resistance to ribosome-targeting agents than those lacking PA5471 or MexXY, and this decrease was observed whether functional PA5471/MexXY was present or not.Multidrug efflux systems of the resistance-nodulation-division (RND) family contribute significantly to intrinsic and acquired resistance to antimicrobials in a number of gram-negative bacteria (43, 45). Despite their significance as determinants of antibiotic resistance, however, RND-type multidrug exporters also, in many instances, accommodate biocides (42, 45), organic solvents (48), detergents (43), including bile salts (9,18,46,60), toxic fatty acids/lipids (54), and in some instances, plant-derived antimicrobials (phytoalexins and isoflavonoids) (7, 39), metabolic inhibitors (52), organometallic compounds (tributyltin) (25), quorum-sensing effector molecules (13,26,40), and, possibly, virulence factors (21) in addition to antibiotics. Clearly, RND pumps can and do function as other than antibiotic exporters.Pseudomonas aeruginosa expresses several three-component RND-type multidrug efflux systems, among which four, MexAB-

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Section: Resultssupporting

confidence: 73%

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confidence: 99%

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Antibiotic Inducibility of the MexXY Multidrug Efflux System of Pseudomonas aeruginosa : Involvement of the Antibiotic-Inducible PA5471 Gene Product

2006

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“…Pseudomonas aeruginosa is an opportunistic human pathogen characterized by an innate resistance to multiple classes of antimicrobials (11), attributable in part to a family of broadly specific, so-called multidrug efflux systems (23,24) that work synergistically with low outer membrane permeability (9,19) to limit antimicrobial accumulation in this organism. Several multidrug efflux systems in P. aeruginosa have been described to date (23), although the major system contributing to intrinsic multidrug resistance is encoded by the mexAB-oprM operon (10,18,26).…”

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Mutations in PA3574 ( nalD ) Lead to Increased MexAB-OprM Expression and Multidrug Resistance in Laboratory and Clinical Isolates of Pseudomonas aeruginosa

Sobel

Hocquet

Cao

et al. 2005

Antimicrob Agents Chemother

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Mutations in genes mexR and nalC have previously been shown to drive overexpression of the MexAB-OprM multidrug efflux system in Pseudomonas aeruginosa. A transposon insertion multidrug-resistant mutant of P. aeruginosa overproducing MexAB-OprM was disrupted in yet a third gene, PA3574, encoding a probable repressor of the TetR/AcrR family that we have dubbed NalD. Clinical strains overexpressing MexAB-OprM but lacking mutations in mexR or nalC were also shown to carry mutations in nalD. Moreover, the cloned nalD gene reduced the multidrug resistance and MexAB-OprM expression of the transposon mutant and clinical isolates, highlighting the significance of the nalD mutations vis-à-vis MexAB-OprM overexpression in these isolates.Pseudomonas aeruginosa is an opportunistic human pathogen characterized by an innate resistance to multiple classes of antimicrobials (11), attributable in part to a family of broadly specific, so-called multidrug efflux systems (23, 24) that work synergistically with low outer membrane permeability (9, 19) to limit antimicrobial accumulation in this organism. Several multidrug efflux systems in P. aeruginosa have been described to date (23), although the major system contributing to intrinsic multidrug resistance is encoded by the mexAB-oprM operon (10, 18, 26). MexAB-OprM exports a wide variety of antimicrobials, including most classes of antibiotics, biocides, dyes, detergents, organic solvents (i.e., aromatic hydrocarbons; reviewed in reference 23]), and homoserine lactones associated with quorum sensing (8,22). The last play a role in cell densitydependent expression of a number of virulence factors in P. aeruginosa, and thus, the activity of this efflux system can influence virulence (30). Indeed, a recent study suggests that the MexAB-OprM efflux system of P. aeruginosa promotes the release of a molecule(s) ultimately important for the virulence of this organism (12). The observation that MexAB-OprM hyperexpression in nalB strains impairs fitness and virulence (30) also suggests that this efflux system has a physiological role in P. aeruginosa independent of antimicrobial efflux and resistance. Consistent with this, mutants hyperexpressing MexABOprM were readily selected in vivo in a rat model of acute P. aeruginosa pneumonia in the absence of any antibiotic selection (16). The specific nature of the selective in vivo growth advantage provided by this efflux system is, however, unknown.Hyperproduction of MexAB-OprM has been documented in lab and clinical multidrug-resistant isolates carrying lesions in the mexR gene (4,15,20,28,35,37) (so-called nalB mutants [21]), encoding a repressor of mexAB-oprM expression (27, 35).MexAB-OprM hyperexpression also occurs independently of mutations in mexR or the mexR and mexAB-oprM promoter regions (35, 37). These so-called nalC mutants (5, 20, 35) carry a mutation in a recently identified gene (PA3721, also known as nalC) that encodes a TetR family repressor of an adjacent two-gene operon, PA3720-PA3719 (5). It is, in fact, the increased express...

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“…Several RND family multidrug efflux systems have been described in Pseudomonas aeruginosa, although the major system contributing to intrinsic multidrug resistance is encoded by the mexAB-oprM operon (16,17). The MexAB-OprM efflux system consists of an inner membrane drug-proton antiporter (the RND component) (MexB), an outer membrane channel-forming component (OprM), and a periplasmic membrane fusion protein (MFP) (MexA) (16,17).…”

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confidence: 99%

Interaction of the MexA and MexB Components of the MexAB-OprM Multidrug Efflux System of Pseudomonas aeruginosa : Identification of MexA Extragenic Suppressors of a T578I Mutation in MexB

Nehme

Poole

2005

Antimicrob Agents Chemother

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Pseudomonas aeruginosa is an opportunistic human pathogen characterized by an innate resistance to multiple antimicrobials (6), resistance increasingly attributable, at least in part, to the operation of broadly specific, multidrug efflux systems of the resistance-nodulation-division (RND) family (16). Several RND family multidrug efflux systems have been described in Pseudomonas aeruginosa, although the major system contributing to intrinsic multidrug resistance is encoded by the mexAB-oprM operon (16, 17). The MexAB-OprM efflux system consists of an inner membrane drug-proton antiporter (the RND component) (MexB), an outer membrane channel-

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Efflux Pumps

Cited by 29 publications

References 238 publications

Antibiotic Inducibility of the MexXY Multidrug Efflux System of Pseudomonas aeruginosa : Involvement of the Antibiotic-Inducible PA5471 Gene Product

Antibiotic Inducibility of the MexXY Multidrug Efflux System of Pseudomonas aeruginosa : Involvement of the Antibiotic-Inducible PA5471 Gene Product

Mutations in PA3574 ( nalD ) Lead to Increased MexAB-OprM Expression and Multidrug Resistance in Laboratory and Clinical Isolates of Pseudomonas aeruginosa

Interaction of the MexA and MexB Components of the MexAB-OprM Multidrug Efflux System of Pseudomonas aeruginosa : Identification of MexA Extragenic Suppressors of a T578I Mutation in MexB

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