Team Resist UMR1184 Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB), 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 (IMVA-HB), 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.
Lancet Microbe. 2024 Jun;5(6):e547-e558. doi: 10.1016/S2666-5247(23)00407-X. Epub 2024 Apr 25.
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.
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.
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.
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.
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摩根菌属是一种机会性病原体，参与多种感染。对多种抗生素（包括黏菌素）的固有耐药性与碳青霉烯酶产生菌的出现相结合，减少了有效的抗菌药物数量。本研究旨在描述与耐碳青霉烯摩根菌属传播相关的遗传特征。
这项比较基因组研究包括 2013 年 1 月 1 日至 2021 年 3 月 1 日期间，法国国家参考中心（NRC；n=68）和欧洲七个国家的欧洲抗菌药物耐药性参考中心（n=104）收集的广泛耐药摩根菌属分离株，以及来自加拿大的一个分离株、巴黎巴斯德研究所收藏的两个参考株（法国）和来自比塞特尔医院（克里姆林比塞特尔，法国）的两个对黏菌素敏感的分离株。通过全基因组测序、药敏试验和生化试验对分离株进行了特征描述。还包括来自 GenBank 的 103 个完整基因组进行基因组分析，包括系统发育和核心基因组和耐药组的确定。通过平均核苷酸同一性（ANI）对不同物种或亚种之间的遗传距离进行分析。通过脂质 A 的遗传分析与质谱联用，研究了多粘菌素固有耐药机制。
对 275 个分离株的距离分析通过 ANI 确定了三个组：嗜冷摩根菌、摩根摩根亚种西博尼和摩根摩根亚种摩根，核心基因组最大似然系统发育树显示，摩根摩根分离株可分为四个亚群。基于这些发现和分离株之间的表型差异，我们提出了摩根菌属的改良分类法，包括四个种，嗜冷摩根菌、西博尼摩根菌、摩根摩根和一个由独特的环境分离株代表的新种。我们建议摩根摩根包括两个亚种：摩根摩根亚种摩根（最常见）和摩根摩根亚种中间型。这种改良的分类法得到了四环素固有耐药性的差异和海藻糖同化等代谢途径的保守性的支持，这些途径仅存在于西博尼摩根菌中。碳青霉烯酶产生菌主要存在于 M 摩根亚种摩根的五个高风险克隆中。最常见的碳青霉烯酶对应 NDM-1，其次是 KPC-2 和 OXA-48。在我们从不同欧洲国家收集的包括金属β-内酰胺酶产生菌在内的 172 株广泛耐药摩根菌属分离株中，头孢吡肟-齐巴坦组合是最有效的抗菌药物。脂质 A 分析表明，对黏菌素的固有耐药性与脂质 A 上存在 L-ARA4N 有关。
本研究对我们所知的最广泛的广泛耐药摩根菌属进行了全球特征描述，突出了阐明分类和破译固有耐药机制的必要性，并为进一步的基因组比较铺平了道路。
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