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Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model

Yang Yu, Timothy R Walsh, Run-Shi Yang, Mei Zheng, Meng-Chao Wei, Jon Tyrrell Orcid Logo, Yang Wang, Xiao-Ping Liao, Jian Sun, Ya-Hong Liu

Journal of Antimicrobial Chemotherapy, Volume: 74, Issue: 1, Pages: 87 - 95

Swansea University Author: Jon Tyrrell Orcid Logo

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DOI (Published version): 10.1093/jac/dky413

Abstract

ObjectivesThe emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existin...

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Published in: Journal of Antimicrobial Chemotherapy
ISSN: 0305-7453 1460-2091
Published: Oxford University Press (OUP) 2018
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URI: https://cronfa.swan.ac.uk/Record/cronfa70438
first_indexed 2025-09-21T17:32:24Z
last_indexed 2025-10-31T18:12:02Z
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spelling 2025-10-30T10:43:19.3841959 v2 70438 2025-09-21 Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model ad510c73555adf718387af219e235a6e 0000-0001-8565-2590 Jon Tyrrell Jon Tyrrell true false 2025-09-21 MEDS ObjectivesThe emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes.MethodsTo comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose–response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs).ResultsCombinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs.ConclusionsThe synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli. Journal Article Journal of Antimicrobial Chemotherapy 74 1 87 95 Oxford University Press (OUP) 0305-7453 1460-2091 20 10 2018 2018-10-20 10.1093/jac/dky413 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University This work was supported by the General Program of National Natural Science Foundation of China (Grant No. 31772793), and the Key Program of the National Natural Science Foundation of China (Grant No. 31730097). Y. Y. was funded by the Graduate Student Overseas Study Program of South China Agricultural University (Grant No. 2017LHPY026). 2025-10-30T10:43:19.3841959 2025-09-21T18:18:29.2369717 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Yang Yu 1 Timothy R Walsh 2 Run-Shi Yang 3 Mei Zheng 4 Meng-Chao Wei 5 Jon Tyrrell 0000-0001-8565-2590 6 Yang Wang 7 Xiao-Ping Liao 8 Jian Sun 9 Ya-Hong Liu 10
title Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model
spellingShingle Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model
Jon Tyrrell
title_short Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model
title_full Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model
title_fullStr Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model
title_full_unstemmed Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model
title_sort Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model
author_id_str_mv ad510c73555adf718387af219e235a6e
author_id_fullname_str_mv ad510c73555adf718387af219e235a6e_***_Jon Tyrrell
author Jon Tyrrell
author2 Yang Yu
Timothy R Walsh
Run-Shi Yang
Mei Zheng
Meng-Chao Wei
Jon Tyrrell
Yang Wang
Xiao-Ping Liao
Jian Sun
Ya-Hong Liu
format Journal article
container_title Journal of Antimicrobial Chemotherapy
container_volume 74
container_issue 1
container_start_page 87
publishDate 2018
institution Swansea University
issn 0305-7453
1460-2091
doi_str_mv 10.1093/jac/dky413
publisher Oxford University Press (OUP)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 0
active_str 0
description ObjectivesThe emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes.MethodsTo comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose–response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs).ResultsCombinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs.ConclusionsThe synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.
published_date 2018-10-20T05:30:53Z
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score 11.089386

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