Yan Zhu1, Irene Galani2, Ilias Karaiskos3, Jing Lu4, Su Mon Aye5, Jiayuan Huang6, Heidi H Yu7, Tony Velkov8, Helen Giamarellou9, Jian Li10. 1. Monash Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne 3800, Australia. Electronic address: yan.zhu@monash.edu. 2. Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: egalani@med.uoa.gr. 3. First Department of Internal Medicine - Infectious Diseases, Hygeia General Hospital, Athens, Greece. Electronic address: ikaraiskos@hygeia.gr. 4. Monash Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne 3800, Australia. Electronic address: jing.lu2@monash.edu. 5. Monash Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne 3800, Australia. Electronic address: su.aye@monash.edu. 6. Monash Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne 3800, Australia. Electronic address: jiayuan.huang@monash.edu. 7. Monash Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne 3800, Australia. Electronic address: heidi.yu@monash.edu. 8. Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne 3010, Australia. Electronic address: tony.velkov@unimelb.edu.au. 9. First Department of Internal Medicine - Infectious Diseases, Hygeia General Hospital, Athens, Greece. Electronic address: e.giamarellou@hygeia.gr. 10. Monash Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne 3800, Australia. Electronic address: jian.li@monash.edu.
Abstract
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.
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.
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