An Extended Reservoir of Class-D Beta-Lactamases in Non-Clinical Bacterial Strains.

OXA; antimicrobial resistance; beta-lactamase; carbapenemase; phylogenetic classification; sequence clustering; Anti-Bacterial Agents; Bacterial Proteins; Carbapenems; beta-Lactamases; Oxacillin; Anti-Bacterial Agents/pharmacology; Bacteria/genetics; Bacteria/metabolism; Bacterial Proteins/metabolism; Humans; Microbial Sensitivity Tests; Phylogeny; Carbapenems/pharmacology; beta-Lactamases/genetics; Physiology; Ecology; Immunology and Microbiology (all); Genetics; Microbiology (medical); Cell Biology; Infectious Diseases; General Immunology and Microbiology

Abstract :

[en] Bacterial genes coding for antibiotic resistance represent a major issue in the fight against bacterial pathogens. Among those, genes encoding beta-lactamases target penicillin and related compounds such as carbapenems, which are critical for human health. Beta-lactamases are classified into classes A, B, C, and D, based on their amino acid sequence. Class D enzymes are also known as OXA beta-lactamases, due to the ability of the first enzymes described in this class to hydrolyze oxacillin. While hundreds of class D beta-lactamases with different activity profiles have been isolated from clinical strains, their nomenclature remains very uninformative. In this work, we have carried out a comprehensive survey of a reference database of 80,490 genomes and identified 24,916 OXA-domain containing proteins. These were deduplicated and their representative sequences clustered into 45 non-singleton groups derived from a phylogenetic tree of 1,413 OXA-domain sequences, including five clusters that include the C-terminal domain of the BlaR membrane receptors. Interestingly, 801 known class D beta-lactamases fell into only 18 clusters. To probe the unknown diversity of the class, we selected 10 protein sequences in 10 uncharacterized clusters and studied the activity profile of the corresponding enzymes. A beta-lactamase activity could be detected for seven of them. Three enzymes (OXA-1089, OXA-1090 and OXA-1091) were active against oxacillin and two against imipenem. These results indicate that, as already reported, environmental bacteria constitute a large reservoir of resistance genes that can be transferred to clinical strains, whether through plasmid exchange or hitchhiking with the help of transposase genes. IMPORTANCE The transmission of genes coding for resistance factors from environmental to nosocomial strains is a major component in the development of bacterial resistance toward antibiotics. Our survey of class D beta-lactamase genes in genomic databases highlighted the high sequence diversity of the enzymes that are able to recognize and/or hydrolyze beta-lactam antibiotics. Among those, we could also identify new beta-lactamases that are able to hydrolyze carbapenems, one of the last resort antibiotic families used in human antimicrobial chemotherapy. Therefore, it can be expected that the use of this antibiotic family will fuel the emergence of new beta-lactamases into clinically relevant strains.

Research Center/Unit :

InBios - Integrative Biological Sciences - ULiège

Disciplines :

Biochemistry, biophysics & molecular biology
Genetics & genetic processes
Microbiology

Author, co-author :

Lupo, Valérian ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)

Mercuri, Paola ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)

Frère, Jean-Marie ; Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques

Joris, Bernard ; Université de Liège - ULiège > Département des sciences de la vie

Galleni, Moreno ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)

Baurain, Denis ^✱; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)

Kerff, Frédéric ^✱; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)

^✱ These authors have contributed equally to this work.

Language :

English

Title :

An Extended Reservoir of Class-D Beta-Lactamases in Non-Clinical Bacterial Strains.

Publication date :

2022

Journal title :

Microbiology Spectrum

eISSN :

2165-0497

Publisher :

American Society for Microbiology, United States

Volume :

Issue :

Pages :

e0031522

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://journals.asm.org/doi/pdf/10.1128/spectrum.00315-22

Funders :

FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture
FPS Health Federal Public Service Health, Food Chain Safety and Environment
ULiège - University of Liège
F.R.S.-FNRS - Fonds de la Recherche Scientifique

Funding number :

RF 17/6317 RU-BLA-ESBL-CPE; SFRD-12/04; J.0080.15

Funding text :

V.L. is supported by a Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture (FRIA) fellowship of the FRS-FNRS. F.K. is a research associate of the FRS-FNRS. M.G. and P.S.M. were supported by the Belgian Federal Public Service Health, Food Chain Safety and Environment (Grant No. RF 17/6317 RU-BLA-ESBL-CPE). Computational resources were provided through two grants to DB (University of Liège “Crédit de démarrage 2012” SFRD-12/04; FRS-FNRS “Crédit de recherche 2014” CDR J.0080.15). We thank Mohammed Terrak and Adrien Boes for useful advice at the initial stage of the project and Hiba Jabri for her help with the OBO dictionary.

Data Set :

https://doi.org/10.6084/m9.figshare.18544955

Available on ORBi :

since 17 June 2022

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