Image_1_Acquisition of Tigecycline Resistance by Carbapenem-Resistant Klebsiella pneumoniae Confers Collateral Hypersensitivity to Aminoglycosides.tif
Tigecycline is a last-resort antibiotic for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). This study aimed to broaden our understanding of the acquisition of collateral hypersensitivity by CRKP, as an evolutionary trade-off of developing resistance to tigecycline. Experimental induction of tigecycline resistance was conducted with tigecycline-sensitive CRKP clinical isolates. Antimicrobial susceptibility testing, microbial fitness assessment, genotypic analysis and full-genome sequencing were carried out for these clinical isolates and their resistance-induced descendants. We found that tigecycline resistance was successfully induced after exposing CRKP clinical isolates to tigecycline at gradually increased concentrations, at a minor fitness cost of bacterial cells. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) found higher expression of the efflux pump gene acrB (5.3–64.5-fold) and its regulatory gene ramA (7.4–65.8-fold) in resistance-induced strains compared to that in the tigecycline-sensitive clinical isolates. Stable hypersensitivities to aminoglycosides and other antibiotics were noticed in resistance-induced strains, showing significantly lowered MICs (X 4 – >500 times). Full genome sequencing and plasmid analysis suggested the induced collateral hypersensitivity might be multifaceted, with the loss of an antimicrobial resistance (AMR) plasmid being a possible major player. This study rationalized the sequential combination of tigecycline with aminoglycosides for the treatment of CRKP infections.
History
References
- https://doi.org//10.1093/molbev/msx158
- https://doi.org//10.1128/AAC.00156-11
- https://doi.org//10.1371/journal.pone.0175140
- https://doi.org//10.1093/jac/dkp498
- https://doi.org//10.1086/518605
- https://doi.org//10.3389/fmicb.2018.00648
- https://doi.org//10.1111/j.1469-0691.2006.01578.x
- https://doi.org//10.1371/journal.pone.0165019
- https://doi.org//10.1128/mSphere.00024-19
- https://doi.org//10.1016/j.copbio.2018.01.026
- https://doi.org//10.1093/jac/dku432
- https://doi.org//10.1371/journal.pone.0119064
- https://doi.org//10.1038/s41564-019-0445-2
- https://doi.org//10.1128/AAC.00085-10
- https://doi.org//10.1093/jac/dkq108
- https://doi.org//10.1128/genomeA.01337-14
- https://doi.org//10.1128/AAC.01503-16
- https://doi.org//10.1016/j.ijantimicag.2016.07.008
- https://doi.org//10.1007/s11427-011-4230-6
- https://doi.org//10.1111/eva.12903
- https://doi.org//10.1371/journal.pbio.3000515
- https://doi.org//10.1128/AAC.03053-14
- https://doi.org//10.1016/j.tim.2015.02.009
- https://doi.org//10.1586/eri.12.162
- https://doi.org//10.1016/j.jinf.2009.02.009
- https://doi.org//10.1093/jac/dks535
- https://doi.org//10.1007/s10096-011-1481-x
- https://doi.org//10.1590/S1517-83822013000200015
- https://doi.org//10.1016/j.diagmicrobio.2012.12.004
- https://doi.org//10.1371/journal.pone.0233313
- https://doi.org//10.1038/s41564-019-0496-4
- https://doi.org//10.1016/j.ijantimicag.2012.09.005
- https://doi.org//10.1093/jac/dkt235
- https://doi.org//10.1128/AAC.01803-13
- https://doi.org//10.1016/j.idc.2020.06.002
- https://doi.org//10.1093/jac/dkl514
- https://doi.org//10.1016/j.mib.2018.04.004
- https://doi.org//10.1099/jmm.0.000299
- https://doi.org//10.1016/j.jgar.2017.10.017
- https://doi.org//10.1038/s41426-018-0129-7
- https://doi.org//10.1128/AAC.02045-12
- https://doi.org//10.1371/journal.pone.0115185
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