Acquired carbapenemase in Acinetobacter during the pre-antibiotic era
Authors: Rémy A Bonnin, Laurent Dortet, Thierry Naas
Journal: The Lancet Microbe (2021)

Acinetobacter species are considered dreadful pathogens for patients in the intensive care unit as they are often multidrug resistant (MDR), leading to difficult-to-treat infections and, occasionally, therapeutic dead ends. Carbapenem-resistant Acinetobacter are in the top position of "the WHO priority pathogens", for which novel antibiotics are desperately needed. The carbapenem-resistance is mostly due to the acquisition of β-lactam-inactivating enzyme, carbapenemase. Acinetobacter indicus, a novel species initially described in 2012 from a polluted dumpsite in India,1Malhotra J Anand S Jindal S Rajagopal R Lal R Acinetobacter indicus sp. nov., isolated from a hexachlorocyclohexane dump site.Int J Syst Evol Microbiol. 2012; 62: 2883-2890Crossref PubMed Scopus (41) Google Scholar has since been identified in human and animal samples, including several OXA-23-producing isolates.2Bonnin RA Poirel L van der Reijden TJK Dijkshoorn L Lescat M Nordmann P Carbapenem resistance in a human clinical isolate identified to be closely related to Acinetobacter indicus.Int J Antimicrob Agents. 2014; 44: 345-350Crossref PubMed Scopus (4) Google Scholar, 3Klotz P Göttig S Leidner U Semmler T Scheufen S Ewers C Carbapenem-resistance and pathogenicity of bovine Acinetobacter indicus-like isolates.PLoS One. 2017; 12e0171986Crossref PubMed Scopus (14) Google Scholar The strain, A indicus CIP 53·82, was already MDR and exhibited minimal inhibitory concentrations of amoxicillin and ticarcillin at >256 mg/L, ceftazidime at 2 mg/L, and imipenem at 8 mg/L. Sequence analysis revealed the presence of blaOXA–58, a carbapenemase gene, a result that triggered our interest, as in the year 1953, no active β-lactam was commercially available against Acinetobacter species. The blaOXA-58 gene was initially identified in France in 2003, and has since been described worldwide, mostly in Acinetobacter species, surrounded by two copies of the insertion sequence, ISAba3, which are involved in gene expression.4Cameranesi MM Morán-Barrio J Limansky AS Repizo GD Viale AM Site-specific recombination at XerC/D sites mediates the formation and resolution of plasmid co-integrates carrying a blaOXA-58- and TnaphA6-resistance module in Acinetobacter baumannii.Front Microbiol. 2018; 9: 66Crossref PubMed Scopus (34) Google Scholar XerC and XerD recombination sites, which bracket this structure, are likely to be involved in its mobilisation.4Cameranesi MM Morán-Barrio J Limansky AS Repizo GD Viale AM Site-specific recombination at XerC/D sites mediates the formation and resolution of plasmid co-integrates carrying a blaOXA-58- and TnaphA6-resistance module in Acinetobacter baumannii.Front Microbiol. 2018; 9: 66Crossref PubMed Scopus (34) Google Scholar In A indicus CIP 53·82 strains, the blaOXA-58 gene is carried by a plasmid of 43 103 base pairs in size. This plasmid encodes proteins that code for mobilisation and replication functions (appendix). A search for homology showed weak identity between this plasmid and plasmids available in the Genbank database. Two copies of the ISAba3 sequence were identified surrounding the blaOXA-58 gene, which were bracketed by two XerC and XerD recombination sites, showing the acquisition of blaOXA-58 (appendix). Of note, the ISAba3 sequence upstream of the blaOXA-58 gene is truncated by recombination sites, which indicates that plasmid acquisition of the ISAba3-blaOXA-58-ISAba3 structure likely occurred before the year 1953. Here, we described the blaOXA-58 gene in A indicus CIP 53·82 strain from the year 1953, which was acquired before the commercialisation of any β-lactam with activity against Acinetobacter species. To the best of our knowledge, the observation of the early acquisition of a β-lactamase before the commercial use of its antimicrobial target was only observed with TEM-1 penicillinase in Salmonella species in the early 1960s,5Tran-Dien A Le Hello S Bouchier C Weill FX Early transmissible ampicillin resistance in zoonotic Salmonella enterica serotype Typhimurium in the late 1950s: a retrospective, whole-genome sequencing study.Lancet Infect Dis. 2018; 18: 207-214Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar which corresponds to a few years before the availability of ampicillin (in the year 1962). Here, this isolate corresponds to the oldest described carbapenemase, at least 32 years before the commercialisation of the first carbapenem. This study highlights again that antimicrobial resistance is pre-existing in nature, and that antibiotic use is responsible for its selection and dissemination. We declare no competing interests. Download .pdf (.31 MB) Help with pdf files Supplementary appendix