High prevalence of mgrB-mediated colistin resistance among carbapenem-resistant Klebsiella pneumoniae is associated with biofilm formation, and can be overcome by colistin-EDTA combination therapy

Aye Mya Sithu Shein, Dhammika Leshan Wannigama, Paul G. Higgins, Cameron Hurst, Shuichi Abe, Parichart Hongsing, Naphat Chantaravisoot, Thammakorn Saethang, Sirirat Luk-in, Tingting Liao, Sumanee Nilgate, Ubolrat Rirerm, Naris Kueakulpattana, Sukrit Srisakul, Apichaya Aryukarn, Matchima Laowansiri, Lee Yin Hao, Manta Yonpiam, Naveen Kumar Devanga Ragupathi, Teerasit TechawiwattanaboonNatharin Ngamwongsatit, Mohan Amarasiri, Puey Ounjai, Rosalyn Kupwiwat, Phatthranit Phattharapornjaroen, Vishnu Nayak Badavath, Asada Leelahavanichkul, Anthony Kicic, Tanittha Chatsuwan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The global prevalence of colistin-resistant Klebsiella pneumoniae (ColRkp) facilitated by chromosomal and plasmid-mediated Ara4N or PEtN-remodeled LPS alterations has steadily increased with increased colistin usage for treating carbapenem-resistant K. pneumoniae (CRkp). Our study demonstrated the rising trend of ColRkp showing extensively and pandrug-resistant characteristics among CRkp, with a prevalence of 28.5%, which was mediated by chromosomal mgrB, pmrB, or phoQ mutations (91.5%), and plasmid-mediated mcr-1.1, mcr-8.1, mcr-8.2 alone or in conjunction with R256G PmrB (8.5%). Several genetic alterations in mgrB (85.1%) with increased expressions of Ara4N-related phoPQ and pmrK were critical for establishing colistin resistance in our isolates. In this study, we discovered the significant associations between extensively drug-resistant bacteria (XDR) and pandrug-resistant bacteria (PDR) ColRkp in terms of moderate, weak or no biofilm-producing abilities, and altered expressions of virulence factors. These ColRkp would therefore be very challenging to treat, emphasizing for innovative therapy to combat these infections. Regardless of the underlying colistin-resistant mechanisms, colistin-EDTA combination therapy in this study produced potent synergistic effects in both in vitro and in vivo murine bacteremia, with no ColRkp regrowth and improved animal survival, implying the significance of colistin-EDTA combination therapy as systemic therapy for unlocking colistin resistance in ColRkp-associated bacteremia.

    Original languageEnglish
    Article number12939
    Pages (from-to)1-19
    Number of pages19
    JournalScientific Reports
    Volume12
    Issue number1
    DOIs
    Publication statusPublished - Dec 2022

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