Dissemination of International Clone II<i>Acinetobacter baumannii</i>Strains Coproducing OXA-23 Carbapenemase and 16S rRNA Methylase ArmA in Athens, Greece

Nafplioti, Konstantina; Galani, Irene; Angelidis, E.; Adamou, Panagiota; Moraitou, Eleni; Giannopoulou, Panagiota; Chra, Paraskevi; Damala, Maria; Vogiatzakis, Evangellos; Trikka-Graphakos, Eleftheria; Baka, Vasiliki; Prifti, Eleni; Antoniadou, Anastasia; Souli, María

doi:10.1089/mdr.2019.0075

Cited by 14 publications

(10 citation statements)

References 25 publications

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“…This may suggest that A. baumannii infections, which tend to be notoriously difficult to treat and are often classified as pan-aminoglycoside resistant due to the high prevalence of RMTases, would remain susceptible to apramycin treatment. Indeed, this genotypic observation corresponds well to previous phenotypic studies with A. baumannii clinical isolates [ 11 , 20 , 26 ].…”

Section: Discussionsupporting

confidence: 90%

“…Apramycin has been described by several independent research groups as an aminoglycoside antibiotic that evades almost all aminoglycoside-resistance mechanisms typically encountered in clinical settings, and consequently demonstrated phenotypic coverage of multidrug-resistant pathogens superior to that of other aminoglycosides [ 9 , 11 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. It was, therefore, surprising that one study reported an aac(3)-IV annotation in 9 out of 98 (9.2%) Enterobacterales isolates in a preselected panel of drug-resistant human clinical isolates [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Plattner

Gysin

Haldimann

et al. 2020

IJMS

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Aminoglycoside antibiotics are powerful bactericidal therapeutics that are often used in the treatment of critical Gram-negative systemic infections. The emergence and global spread of antibiotic resistance, however, has compromised the clinical utility of aminoglycosides to an extent similar to that found for all other antibiotic-drug classes. Apramycin, a drug candidate currently in clinical development, was suggested as a next-generation aminoglycoside antibiotic with minimal cross-resistance to all other standard-of-care aminoglycosides. Here, we analyzed 591,140 pathogen genomes deposited in the NCBI National Database of Antibiotic Resistant Organisms (NDARO) for annotations of apramycin-resistance genes, and compared them to the genotypic prevalence of carbapenem resistance and 16S-rRNA methyltransferase (RMTase) genes. The 3-N-acetyltransferase gene aac(3)-IV was found to be the only apramycin-resistance gene of clinical relevance, at an average prevalence of 0.7%, which was four-fold lower than that of RMTase genes. In the important subpopulation of carbapenemase-positive isolates, aac(3)-IV was nine-fold less prevalent than RMTase genes. The phenotypic profiling of selected clinical isolates and recombinant strains expressing the aac(3)-IV gene confirmed resistance to not only apramycin, but also gentamicin, tobramycin, and paromomycin. Probing the structure–activity relationship of such substrate promiscuity by site-directed mutagenesis of the aminoglycoside-binding pocket in the acetyltransferase AAC(3)-IV revealed the molecular contacts to His124, Glu185, and Asp187 to be equally critical in binding to apramycin and gentamicin, whereas Asp67 was found to be a discriminating contact. Our findings suggest that aminoglycoside cross-resistance to apramycin in clinical isolates is limited to the substrate promiscuity of a single gene, rendering apramycin best-in-class for the coverage of carbapenem- and aminoglycoside-resistant bacterial infections.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Plattner

Gysin

Haldimann

et al. 2020

IJMS

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“…Studies reported from Spain and Greece shows 100% and 99.4% A. baumannii isolates belonged to international clone II, respectively. 30,70 The results of our research also indicate that SG1 is more common among other groups.…”

Section: Discussionsupporting

confidence: 70%

Genetic characterization of extensive drug resistant Acinetobacter baumannii: an appalling impediment

Abbaszadeh¹,

Hasani²,

Rezaee³

et al. 2021

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Introduction:Acinetobacter baumannii infections are a growing public-health concern. The bacterium’s potentiality to acquire resistance to a number of commonly used antibiotics has turned it into a formidable pathogen. Aims: Molecular characterization of extensive drug resistant (XDR) typing of A. baumannii clinical isolates by polymerase chain reaction. Materials and methods: Thirty XDR A. baumannii were investigated for the presence of genes encoding carbapenemase resistance, biofilm capacity, autoinducer synthase, virulence and surface motility by polymerase chain reaction (PCR). Later, the isolates were typed by plasmid-based replicon (Rep) (PBRT) and trilocus sequence typing. Results: All 30 XDR A. baumannii strains displayed genes related to surface motility, autoinducer synthase, virulence determinant, biofilm related genes except PER, and bap, the frequency of which was 83.3% and 76.6%, respectively. Analysis of rep genes showed highest frequency of rep6 and rep2 genes, with frequency of 75% and 65%, respectively. All XDR A. baumannii strains belonged to SG I (European clone II) group. Conclusions: Our results show the extraordinary plasticity of XDR A. baumannii and suggest that the strains have gained endemicity in our hospital, which could be a great concern in the near future.

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“…PTA results were only slightly affected for dose variations between 20 and 35 mg/kg (Supplementary Figure S3). [12,15,20,21]. Genetic information was unavailable for the isolates tested in this study, but it is reasonable to assume that the single clinical isolate resistant to EBL-1003 carries the aac(3)-IV resistance gene, which has been described as the only apramycin resistance mechanism of clinical relevance [12,13].…”

Section: Pkpd and Probability Of Target Attainment (Pta) Analysismentioning

confidence: 97%

“…Modification by the N-acetyl-transferase AAC(3)-IV remains the sole clinically relevant resistance mechanism for apramycin[12,13]. Several research groups have independently reported outstanding in-vitro activity of apramycin against highly drug-resistant clinical isolates of A. baumannii[12,14,15].Based on these encouraging reports on apramycin activity, we sought proof of concept for the therapeutic efficacy of EBL-1003 in pulmonary infections, and insights into the lung penetration and therefore probability of target attainment (PTA) in respiratory CRAB infection.J o u r n a l P r e -p r o o f…”

mentioning

confidence: 99%

Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice

Becker

Aranzana-Climent

Cao

et al. 2021

Clinical Microbiology and Infection

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Dissemination of International Clone IIAcinetobacter baumanniiStrains Coproducing OXA-23 Carbapenemase and 16S rRNA Methylase ArmA in Athens, Greece

Cited by 14 publications

References 25 publications

Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Genetic characterization of extensive drug resistant Acinetobacter baumannii: an appalling impediment

Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice

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