Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment - Journal of Infection

Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment - Journal of Infection

Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment

Yan Zhua,Email the author Yan Zhu

, 

Irene Galanib,Email the author Irene Galani

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Ilias Karaiskosc,Email the author Ilias Karaiskos

, 

Jing Lua,Email the author Jing Lu

, 

Su Mon Ayea,Email the author Su Mon Aye

, 

Jiayuan Huanga,Email the author Jiayuan Huang

, 

Heidi H. Yua,Email the author Heidi H. Yu

, 

Tony Velkovd,Email the author Tony Velkov

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Helen Giamarellouc,Email the author Helen Giamarellou

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Jian Lia,,Correspondence information about the author Jian Li

Highlights

• •16 K. pneumoniae isolates were from 8 patients before and after colistin treatment.
• •Totally 449 resistance genes were predicted to confer multidrug resistance.
• •An ISKpn26-like element disrupted mgrB in 15 of 16 K. pneumoniae isolates.
• •phoQ mutations in 7 colistin-susceptible K. pneumoniae isolates with disrupted mgrB.
• •Secondary PhoQ mutations occurred in mgrB-disrupted, colistin-resistant isolates.

Summary

Objectives

Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates.

Methods

Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations.

Results

Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P).

Conclusions

This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.