BACKGROUND: Morganella spp are opportunistic pathogens involved in various infections. Intrinsic resistance to multiple antibiotics (including colistin) combined with the emergence of carbapenemase producers reduces the number of active antimicrobials. The aim of this study was to characterise genetic features related to the spread of carbapenem-resistant Morganella spp. METHODS: This comparative genomic study included extensively drug-resistant Morganella spp isolates collected between Jan 1, 2013, and March 1, 2021, by the French National Reference Center (NRC; n=68) and European antimicrobial resistance reference centres in seven European countries (n=104), as well as one isolate from Canada, two reference strains from the Pasteur Institute collection (Paris, France), and two colistin-susceptible isolates from Bicêtre Hospital (Kremlin-Bicêtre, France). The isolates were characterised by whole-genome sequencing, antimicrobial susceptibility testing, and biochemical tests. Complete genomes from GenBank (n=103) were also included for genomic analysis, including phylogeny and determination of core genomes and resistomes. Genetic distance between different species or subspecies was performed using average nucleotide identity (ANI). Intrinsic resistance mechanisms to polymyxins were investigated by combining genetic analysis with mass spectrometry on lipid A. FINDINGS: Distance analysis by ANI of 275 isolates identified three groups: Morganella psychrotolerans, Morganella morganii subspecies sibonii, and M morganii subspecies morganii, and a core genome maximum likelihood phylogenetic tree showed that the M morganii isolates can be separated into four subpopulations. On the basis of these findings and of phenotypic divergences between isolates, we propose a modified taxonomy for the Morganella genus including four species, Morganella psychrotolerans, Morganella sibonii, Morganella morganii, and a new species represented by a unique environmental isolate. We propose that M morganii include two subspecies: M morganii subspecies morganii (the most prevalent) and M morganii subspecies intermedius. This modified taxonomy was supported by a difference in intrinsic resistance to tetracycline and conservation of metabolic pathways such as trehalose assimilation, both only present in M sibonii. Carbapenemase producers were mostly identified among five high-risk clones of M morganii subspecies morganii. The most prevalent carbapenemase corresponded to NDM-1, followed by KPC-2, and OXA-48. A cefepime-zidebactam combination was the most potent antimicrobial against the 172 extensively drug-resistant Morganella spp isolates in our collection from different European countries, which includes metallo-β-lactamase producers. Lipid A analysis showed that the intrinsic resistance to colistin was associated with the presence of L-ARA4N on lipid A. INTERPRETATION: This global characterisation of, to our knowledge, the widest collection of extensively drug-resistant Morganella spp highlights the need to clarify the taxonomy and decipher intrinsic resistance mechanisms, and paves the way for further genomic comparisons. FUNDING: None.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Molecular Microbiology National Medicines Institute Warsaw Poland

German National Reference Centre for Multidrug Resistant Gram Negative Bacteria Department of Medical Microbiology Ruhr University Bochum Bochum Germany

Institut Pasteur Université Paris Cité CNRS UMR3525 Microbial Evolutionary Genomics Paris France

Laboratory for Infectious Diseases and Screening National Institute for Public Health and the Environment Bilthoven Netherlands

MRC Centre for Molecular Bacteriology and Infection Department of Life Sciences Faculty of Natural Sciences Imperial College London London UK

National Institute for Health Research Health Protection Research Unit Reference Unit National Infection Service Public Health England London UK

National Reference Center for Antimicrobial Resistance and Nosocomial Infections Institute for Hygiene Microbiology and Tropical Medicine Ordensklinikum Linz Elisabethinen Linz Austria

National Reference Laboratory for Monitoring of Antimicrobial Resistance in Gram Negative Bacteria CHU Dinant Godinne UCL Namur Yvoir Belgium

Team Resist UMR1184 Immunology of Viral Auto Immune Hematological and Bacterial Diseases INSERM Université Paris Saclay CEA LabEx LERMIT Faculty of Medicine Le Kremlin Bicêtre France

Team Resist UMR1184 Immunology of Viral Auto Immune Hematological and Bacterial Diseases INSERM Université Paris Saclay CEA LabEx LERMIT Faculty of Medicine Le Kremlin Bicêtre France; Associated French National Reference Center for Antibiotic Resistance Carbapenemase Producing Enterobacteriaceae Le Kremlin Bicêtre France

Team Resist UMR1184 Immunology of Viral Auto Immune Hematological and Bacterial Diseases INSERM Université Paris Saclay CEA LabEx LERMIT Faculty of Medicine Le Kremlin Bicêtre France; Associated French National Reference Center for Antibiotic Resistance Carbapenemase Producing Enterobacteriaceae Le Kremlin Bicêtre France; Bacteriology Hygiene Unit Assistance Publique Hôpitaux de Paris AP HP Paris Saclay Bicêtre Hospital Le Kremlin Bicêtre France

Team Resist UMR1184 Immunology of Viral Auto Immune Hematological and Bacterial Diseases INSERM Université Paris Saclay CEA LabEx LERMIT Faculty of Medicine Le Kremlin Bicêtre France; Bacteriology Hygiene Unit Assistance Publique Hôpitaux de Paris AP HP Paris Saclay Bicêtre Hospital Le Kremlin Bicêtre France

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