Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance (2024)

Laborda, P., Lolle, S., Hernando-Amado, S., Alcalde-Rico, M., Aanæs, K., Martínez, J. L., Molin, S. (2024). Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance. Nature Communications, 15(1), Article 2584. https://doi.org/10.1038/s41467-024-46938-w

Laborda, Pablo ; Lolle, Signe ; Hernando-Amado, Sara et al. / Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance. In: Nature Communications. 2024 ; Vol. 15, No. 1.

@article{ea957ca9e8d7477092a8ec3959f807dd,

title = "Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance",

abstract = "Mutations in mexZ, encoding a negative regulator of theexpression of the mexXY efflux pump genes, are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin, mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory, suggesting that their selection during infection may not be necessarily, or only, related to tobramycin therapy. Here, we show that mexZ-mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model, thus colonising the epithelium while being protected against diverse antibiotics. This phenotype is mediated by overexpression of lecA, a quorum sensing-controlled gene, encoding a lectin involved in P. aeruginosa tissue invasiveness. We find that lecA overexpression is caused by a disrupted equilibrium between the overproduced MexXY and another efflux pump, MexAB, which extrudes quorum sensing signals. Our results indicate that mexZ mutations affect the expression of quorum sensing-regulated pathways, thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within patients, something unnoticeable using standard laboratory tests.",

author = "Pablo Laborda and Signe Lolle and Sara Hernando-Amado and Manuel Alcalde-Rico and Kasper Aan{\ae}s and Mart{\'i}nez, {Jos{\'e} Luis} and S{\o}ren Molin and Johansen, {Helle Krogh}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s41467-024-46938-w",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Laborda, P, Lolle, S, Hernando-Amado, S, Alcalde-Rico, M, Aanæs, K, Martínez, JL, Molin, S 2024, 'Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance', Nature Communications, vol. 15, no. 1, 2584. https://doi.org/10.1038/s41467-024-46938-w

Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance. / Laborda, Pablo; Lolle, Signe; Hernando-Amado, Sara et al.
In: Nature Communications, Vol. 15, No. 1, 2584, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance

AU - Laborda, Pablo

AU - Lolle, Signe

AU - Hernando-Amado, Sara

AU - Alcalde-Rico, Manuel

AU - Aanæs, Kasper

AU - Martínez, José Luis

AU - Molin, Søren

AU - Johansen, Helle Krogh

N1 - Publisher Copyright:© The Author(s) 2024.

PY - 2024

Y1 - 2024

N2 - Mutations in mexZ, encoding a negative regulator of theexpression of the mexXY efflux pump genes, are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin, mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory, suggesting that their selection during infection may not be necessarily, or only, related to tobramycin therapy. Here, we show that mexZ-mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model, thus colonising the epithelium while being protected against diverse antibiotics. This phenotype is mediated by overexpression of lecA, a quorum sensing-controlled gene, encoding a lectin involved in P. aeruginosa tissue invasiveness. We find that lecA overexpression is caused by a disrupted equilibrium between the overproduced MexXY and another efflux pump, MexAB, which extrudes quorum sensing signals. Our results indicate that mexZ mutations affect the expression of quorum sensing-regulated pathways, thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within patients, something unnoticeable using standard laboratory tests.

AB - Mutations in mexZ, encoding a negative regulator of theexpression of the mexXY efflux pump genes, are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin, mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory, suggesting that their selection during infection may not be necessarily, or only, related to tobramycin therapy. Here, we show that mexZ-mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model, thus colonising the epithelium while being protected against diverse antibiotics. This phenotype is mediated by overexpression of lecA, a quorum sensing-controlled gene, encoding a lectin involved in P. aeruginosa tissue invasiveness. We find that lecA overexpression is caused by a disrupted equilibrium between the overproduced MexXY and another efflux pump, MexAB, which extrudes quorum sensing signals. Our results indicate that mexZ mutations affect the expression of quorum sensing-regulated pathways, thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within patients, something unnoticeable using standard laboratory tests.

U2 - 10.1038/s41467-024-46938-w

DO - 10.1038/s41467-024-46938-w

M3 - Journal article

C2 - 38519499

AN - SCOPUS:85188426897

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2584

ER -

Laborda P, Lolle S, Hernando-Amado S, Alcalde-Rico M, Aanæs K, Martínez JL et al. Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance. Nature Communications. 2024;15(1):2584. doi: 10.1038/s41467-024-46938-w