A Novel, Integron-Regulated, Class C β-Lactamase

Abstract

AmpC-type β-lactamases severely impair treatment of many bacterial infections, due to their broad spectrum (they hydrolyze virtually all β-lactams, except fourth-generation cephalosporins and carbapenems) and the increasing incidence of plasmid-mediated versions. The original chromosomal AmpCs are often tightly regulated, and their expression is induced in response to exposure to β-lactams. Regulation of mobile ampC expression is in many cases less controlled, giving rise to constitutively resistant strains with increased potential for development or acquisition of additional resistances. We present here the identification of two integron-encoded ampC genes, blaIDC-1 and blaIDC-2 (integron-derived cephalosporinase), with less than 85% amino acid sequence identity to any previously annotated AmpC. While their resistance pattern identifies them as class C β-lactamases, their low isoelectric point (pI) values make differentiation from other β-lactamases by isoelectric focusing impossible. To the best of our knowledge, this is the first evidence of an ampC gene cassette within a class 1 integron, providing a mobile context with profound potential for transfer and spread into clinics. It also allows bacteria to adapt expression levels, and thus reduce fitness costs, e.g., by cassette-reshuffling. Analyses of public metagenomes, including sewage metagenomes, show that the discovered ampCs are primarily found in Asian countries.

Impact of Hospital Wastewater on the Occurrence and Diversity of Beta-Lactamase Genes During Wastewater Treatment with an Emphasis on Carbapenemase Genes: A Metagenomic Approach

“…Beta-lactamase and carbapenemase encoding genes are usually located on plasmids (the structure of which often includes integrons) or in the bacterial chromosome (Papp-Wallace et al, 2016;Perez et al, 2016;Bonomo, 2017). The literature identifies the presence of beta-lactam resistance genes from all Ambler classes in integron gene cassettes in environmental samples such as treated wastewater, sewage sludge, or soil (Gatica et al, 2016;Böhm et al, 2020). Despite sequence differences in the integrase gene, it was described that the same gene cassettes could be found in class 1 and 2 and class 1 and 3 integrons (Carattoli, 2001).…”

Antibiotic resistome from the One-Health perspective: understanding and controlling antimicrobial resistance transmission

“…Three different approaches, including functional metagenomics, shotgun metagenomics, and targeted gene sequencing (amplicon sequencing), have been applied in several studies, considering the trajectory of the studies over the last decade. Metagenomics has been widely used to identify novel ARGs (functional metagenomics) 99 , 108 and ARG variants or genetic contexts of ARGs (targeted gene sequencing) 31 , 41 , 109 , 110 , and to analyze ARGs at the resistome level (shotgun metagenomics) 37 , 111 – 113 . According to specific research purposes, appropriate sequencing platforms, ARG databases, and analysis pipelines should be employed to understand AMR at the resistome level.…”

The Natural History of Integrons

“…Finally, the success of class 1 integrons can be attributed to the significant advantages they provide to their bacterial hosts under antimicrobial selection. Collectively, they have acquired more than 130 different resistance genes [40], with more being continuously discovered [46][47][48][49]. Despite class 1 integrons being able to recognise and integrate a broad range of gene cassettes, there seems to be a preponderance of antimicrobial resistance genes out of the broader diversity of cassette functions that are associated with class 1 integrons [25].…”