Project Title
Unraveling the Emergence and Spread of NDM-Producing Carbapenem-Resistant Enterobacterales (CRE) in Chile: Genomic Insights and Evaluation of Last-Resort Antimicrobials
Partner Organisations
Internal ID
1250588
Principal Investigator
Type
basic research
Status
VIGENTE
Start Date
April 1, 2025
End Date
April 1, 2029
Description
Carbapenemase-producing CRE are consistently categorized as one of the most concerning
multidrug-resistant pathogens worldwide. Among them, New Delhi Metallo-beta-lactamase (NDM)-producing
pathogens are particularly worrisome due to their high potential for dissemination, elevated mortality rates
and scarcity of reliable therapeutic alternatives. Our preliminary data derived from a multicenter network of
tertiary-care hospitals across Chile suggest the molecular epidemiology of CRE is rapidly changing, with a
dramatic surge of NDM-producing-CRE over the last few years. Our analyses suggest this epidemiological
change is occurring in a wide number of bacterial species and across the whole country, likely due to the
successful dissemination of blaNDM-7 that is harbored in plasmids belonging to the IncX3 family. Moreover,
clustering analyses using all publicly available blaNDM-7-harboring plasmids revealed two clusters, one of them
only formed by a group of plasmids from Chilean isolates, suggesting mobile genetic elements spreading
NDM in the country are unique from those reported elsewhere. Hence, we postulate that the multispecies
surge of NDM-producing CRE across Chile is largely driven by the widespread dissemination of highly efficient,
broad-range IncX3 plasmids harboring blaNDM-7 and that blaNDM-7-harboring plasmids circulating in Chile are
unique from those reported elsewhere. In this proposal, we aim to provide a detailed characterization of the
genomic factors underlying the multispecies increase of NDM-producing CRE and to understand the mobile
genetic elements containing blaNDM over time (Aim I). Additionally, our preliminary results using a subset of
our NDM-producing CRE to test the in vitro activity of cefidercol, currently the only two available β-lactam
compounds with antimicrobial activity against NDM-producers, suggest that blaNDM-7 Enterobacterales
circulating in our country exhibit alarmingly high frequencies of hetero-resistance to cefiderocol.
Consequently, we propose to perform a detailed assessment of the in vitro activity of cefiderocol against an
extensive collection of well-characterized NDM-producing CRE and to explore the molecular mechanisms
underlying non-susceptible phenotypes (Aim II). Finally, we will also evaluate the in vitro activity of newer
antimicrobial combinations currently in their late stage of development, including aztreonam-avibactam,
cefepime/zidebactam and cefepime/taniborbactam (Aim II).
Goals: This study aims to 1) characterize the genomic epidemiology of NDM-producing CRE in Chile and
understand the molecular mechanisms driving the expansion of the blaNDM gene, and 2) evaluate the in vitro
activity of newer antimicrobial compounds against clinical NDM-producing CRE isolates in Chile, including
NDM-7 in particular, and explore the mechanisms of non-susceptibility to these cutting-edge newer therapies.
Specific Aim I: To characterize the genomic epidemiology of NDM-producing CRE circulating in Chile and
elucidate the molecular mechanisms driving the rapid expansion of the blaNDM gene across multiple bacterial species.
Specific Aim II: To evaluate the in vitro activity of newer antimicrobial compounds — including cefiderocol,
aztreonam-avibactam, cefepime-taniborbactam, and cefepime-zidebactam — against clinical NDM-producing
CRE isolates circulating in Chile, and explore the molecular mechanisms underlying non-susceptibility to
these last-resort alternatives.
Methods: For the Aim I, we will perform whole-genome sequencing (combination of short-read and longread sequencing) to a large collection of clinical NDM-producing CRE isolates obtained from 11 hospitals
across Chile to then perform different bioinformatic analyses to understand the molecular basis of NDM
dissemination in the country. Analysis will include phylogenomic and phylogeographic reconstructions,
plasmid comparative analyses, Bayesian molecular clock studies, among others. Also, microbiological assays
will be produced to attempt to understand the biological correlate of the different mobile genetic elements
containing the blaNDM gene. For Aim II, we will perform antimicrobial susceptibility assays of NDM-producing
CRE against newer antibiotics, such as cefiderocol, ceftazidime-avibactam, cefepime-zidebactam, and
cefepime-taniborbactam. Details population profile analyses will be performed for cefiderocol to analyze the
prevalence and level of heteroresistance. Finally, genomic data generated in Aim I will be employed to explore
potential mechanisms of resistance in non-susceptible isolates.
Expected Outcomes: We expect to provide a comprehensive understanding of the genomic landscape and
epidemiology of NDM-producing CRE in Chile, identifying key factors contributing to their spread. Additionally,
it will offer critical insights into the efficacy of newer antimicrobial compounds against these pathogens,
particularly against NDM-7 variants, and the underlying mechanisms of resistance. These findings will inform
clinical treatment strategies and guide public health interventions to control the spread of NDM-producing
CRE in Chile.
Significance: Our results will have significant implications for curbing the unfettered spread if NDM and to
inform the future management of CRE infections in Chile and in other regions facing similar challenges.
This research will contribute to the development of more effective diagnostic, therapeutic, and preventative
measures against these formidable pathogens.
multidrug-resistant pathogens worldwide. Among them, New Delhi Metallo-beta-lactamase (NDM)-producing
pathogens are particularly worrisome due to their high potential for dissemination, elevated mortality rates
and scarcity of reliable therapeutic alternatives. Our preliminary data derived from a multicenter network of
tertiary-care hospitals across Chile suggest the molecular epidemiology of CRE is rapidly changing, with a
dramatic surge of NDM-producing-CRE over the last few years. Our analyses suggest this epidemiological
change is occurring in a wide number of bacterial species and across the whole country, likely due to the
successful dissemination of blaNDM-7 that is harbored in plasmids belonging to the IncX3 family. Moreover,
clustering analyses using all publicly available blaNDM-7-harboring plasmids revealed two clusters, one of them
only formed by a group of plasmids from Chilean isolates, suggesting mobile genetic elements spreading
NDM in the country are unique from those reported elsewhere. Hence, we postulate that the multispecies
surge of NDM-producing CRE across Chile is largely driven by the widespread dissemination of highly efficient,
broad-range IncX3 plasmids harboring blaNDM-7 and that blaNDM-7-harboring plasmids circulating in Chile are
unique from those reported elsewhere. In this proposal, we aim to provide a detailed characterization of the
genomic factors underlying the multispecies increase of NDM-producing CRE and to understand the mobile
genetic elements containing blaNDM over time (Aim I). Additionally, our preliminary results using a subset of
our NDM-producing CRE to test the in vitro activity of cefidercol, currently the only two available β-lactam
compounds with antimicrobial activity against NDM-producers, suggest that blaNDM-7 Enterobacterales
circulating in our country exhibit alarmingly high frequencies of hetero-resistance to cefiderocol.
Consequently, we propose to perform a detailed assessment of the in vitro activity of cefiderocol against an
extensive collection of well-characterized NDM-producing CRE and to explore the molecular mechanisms
underlying non-susceptible phenotypes (Aim II). Finally, we will also evaluate the in vitro activity of newer
antimicrobial combinations currently in their late stage of development, including aztreonam-avibactam,
cefepime/zidebactam and cefepime/taniborbactam (Aim II).
Goals: This study aims to 1) characterize the genomic epidemiology of NDM-producing CRE in Chile and
understand the molecular mechanisms driving the expansion of the blaNDM gene, and 2) evaluate the in vitro
activity of newer antimicrobial compounds against clinical NDM-producing CRE isolates in Chile, including
NDM-7 in particular, and explore the mechanisms of non-susceptibility to these cutting-edge newer therapies.
Specific Aim I: To characterize the genomic epidemiology of NDM-producing CRE circulating in Chile and
elucidate the molecular mechanisms driving the rapid expansion of the blaNDM gene across multiple bacterial species.
Specific Aim II: To evaluate the in vitro activity of newer antimicrobial compounds — including cefiderocol,
aztreonam-avibactam, cefepime-taniborbactam, and cefepime-zidebactam — against clinical NDM-producing
CRE isolates circulating in Chile, and explore the molecular mechanisms underlying non-susceptibility to
these last-resort alternatives.
Methods: For the Aim I, we will perform whole-genome sequencing (combination of short-read and longread sequencing) to a large collection of clinical NDM-producing CRE isolates obtained from 11 hospitals
across Chile to then perform different bioinformatic analyses to understand the molecular basis of NDM
dissemination in the country. Analysis will include phylogenomic and phylogeographic reconstructions,
plasmid comparative analyses, Bayesian molecular clock studies, among others. Also, microbiological assays
will be produced to attempt to understand the biological correlate of the different mobile genetic elements
containing the blaNDM gene. For Aim II, we will perform antimicrobial susceptibility assays of NDM-producing
CRE against newer antibiotics, such as cefiderocol, ceftazidime-avibactam, cefepime-zidebactam, and
cefepime-taniborbactam. Details population profile analyses will be performed for cefiderocol to analyze the
prevalence and level of heteroresistance. Finally, genomic data generated in Aim I will be employed to explore
potential mechanisms of resistance in non-susceptible isolates.
Expected Outcomes: We expect to provide a comprehensive understanding of the genomic landscape and
epidemiology of NDM-producing CRE in Chile, identifying key factors contributing to their spread. Additionally,
it will offer critical insights into the efficacy of newer antimicrobial compounds against these pathogens,
particularly against NDM-7 variants, and the underlying mechanisms of resistance. These findings will inform
clinical treatment strategies and guide public health interventions to control the spread of NDM-producing
CRE in Chile.
Significance: Our results will have significant implications for curbing the unfettered spread if NDM and to
inform the future management of CRE infections in Chile and in other regions facing similar challenges.
This research will contribute to the development of more effective diagnostic, therapeutic, and preventative
measures against these formidable pathogens.
Keywords
Fields of Science and Technology (OECD)
Medical and Health sciences
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