Mutations causing low level antibiotic resistance ensure bacterial survival in antibiotic-treated hosts

TY - JOUR

T1 - Mutations causing low level antibiotic resistance ensure bacterial survival in antibiotic-treated hosts

AU - Frimodt-Møller, Jakob

AU - Rossi, Elio

AU - Haagensen, Janus Anders Juul

AU - Falcone, Marilena

AU - Molin, Søren

AU - Johansen, Helle Krogh

PY - 2018

Y1 - 2018

N2 - In 474 genome sequenced Pseudomonas aeruginosa isolates from 34 cystic fibrosis (CF) patients, 40% of these harbor mutations in the mexZ gene encoding a negative regulator of the MexXY-OprM efflux pump associated with aminoglycoside and fluoroquinolone resistance. Surprisingly, resistance to aminoglycosides and fluoroquinolones of mexZ mutants was far below the breakpoint of clinical resistance. However, the fitness increase of the mutant bacteria in presence of the relevant antibiotics, as demonstrated in competition experiments between mutant and ancestor bacteria, showed that 1) very small phenotypic changes cause significant fitness increase with severe adaptive consequences, and 2) standardized phenotypic tests fail to detect such low-level variations. The frequent appearance of P. aeruginosa mexZ mutants in CF patients is directly connected to the intense use of the target antibiotics, and low-level antibiotic resistance, if left unnoticed, can result in accumulation of additional genetic changes leading to high-level resistance.

AB - In 474 genome sequenced Pseudomonas aeruginosa isolates from 34 cystic fibrosis (CF) patients, 40% of these harbor mutations in the mexZ gene encoding a negative regulator of the MexXY-OprM efflux pump associated with aminoglycoside and fluoroquinolone resistance. Surprisingly, resistance to aminoglycosides and fluoroquinolones of mexZ mutants was far below the breakpoint of clinical resistance. However, the fitness increase of the mutant bacteria in presence of the relevant antibiotics, as demonstrated in competition experiments between mutant and ancestor bacteria, showed that 1) very small phenotypic changes cause significant fitness increase with severe adaptive consequences, and 2) standardized phenotypic tests fail to detect such low-level variations. The frequent appearance of P. aeruginosa mexZ mutants in CF patients is directly connected to the intense use of the target antibiotics, and low-level antibiotic resistance, if left unnoticed, can result in accumulation of additional genetic changes leading to high-level resistance.

U2 - 10.1038/s41598-018-30972-y

DO - 10.1038/s41598-018-30972-y

M3 - Journal article

C2 - 30131514

AN - SCOPUS:85051938789

SN - 2045-2322

VL - 8

SP - 1

EP - 13

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 12512

ER -