%A Chen,Hua-le %A Jiang,Yan %A Li,Mei-mei %A Sun,Yao %A Cao,Jian-ming %A Zhou,Cui %A Zhang,Xiao-xiao %A Qu,Yue %A Zhou,Tie-li %D 2021 %J Frontiers in Microbiology %C %F %G English %K Collateral Sensitivity,CRKP,Aminoglycosides,tigecycline,antimicrobial resistance %Q %R 10.3389/fmicb.2021.674502 %W %L %M %P %7 %8 2021-July-02 %9 Original Research %# %! Collateral sensitivity in CRKP %* %< %T Acquisition of Tigecycline Resistance by Carbapenem-Resistant Klebsiella pneumoniae Confers Collateral Hypersensitivity to Aminoglycosides %U https://www.frontiersin.org/articles/10.3389/fmicb.2021.674502 %V 12 %0 JOURNAL ARTICLE %@ 1664-302X %X 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.