TY - JOUR
T1 - 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
AU - Shein, Aye Mya Sithu
AU - Wannigama, Dhammika Leshan
AU - Higgins, Paul G.
AU - Hurst, Cameron
AU - Abe, Shuichi
AU - Hongsing, Parichart
AU - Chantaravisoot, Naphat
AU - Saethang, Thammakorn
AU - Luk-in, Sirirat
AU - Liao, Tingting
AU - Nilgate, Sumanee
AU - Rirerm, Ubolrat
AU - Kueakulpattana, Naris
AU - Srisakul, Sukrit
AU - Aryukarn, Apichaya
AU - Laowansiri, Matchima
AU - Hao, Lee Yin
AU - Yonpiam, Manta
AU - Ragupathi, Naveen Kumar Devanga
AU - Techawiwattanaboon, Teerasit
AU - Ngamwongsatit, Natharin
AU - Amarasiri, Mohan
AU - Ounjai, Puey
AU - Kupwiwat, Rosalyn
AU - Phattharapornjaroen, Phatthranit
AU - Badavath, Vishnu Nayak
AU - Leelahavanichkul, Asada
AU - Kicic, Anthony
AU - Chatsuwan, Tanittha
N1 - Funding Information:
This work was supported by a grant from the 90th Year Anniversary Ratchadapiseksompotch Endowment Fund from the Faculty of Medicine and Graduate School, Chulalongkorn University, Bangkok, Thailand (batch No. 51 (1/65)). Aye Mya Sithu Shein was supported under the Chulalongkorn University Graduate Scholarship Program for ASEAN Countries. Dhammika Leshan Wannigama was supported by Chulalongkorn University Second Century Fund-C2F Fellowship, and the University of Western Australia (Overseas Research Experience Fellowship). For this project Sirirat Luk-in is also funded and supported by National Research Council of Thailand. The sponsor(s) had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Funding Information:
We thank the staff of the bacteriology division, Department of Microbiology at King Chulalongkorn Memorial Hospital, for providing the K. pneumoniae clinical isolates.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135182637&partnerID=8YFLogxK
U2 - 10.1038/s41598-022-17083-5
DO - 10.1038/s41598-022-17083-5
M3 - Article
C2 - 35902639
AN - SCOPUS:85135182637
SN - 2045-2322
VL - 12
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 12939
ER -