Global lessons from antibiotic resistance: metformin-hydrolyzing genes in transposable elements, a new threat for type II diabetic patients?

Abstract

Metformin drug, widely used to treat type II diabetic patients, is a major pharmaceutical pollutant of wastewater and rivers. This environmental exposure has driven the evolution of bacteria, such as Aminobacter and Pseudomonas, to degrade metformin via a Ni{superscript 2}-dependent metformin hydrolase complex (MfmAB). Here we decipher the mechanism of acquisition and horizontal transfer of the mfmAB genes, initially mobilized from Aminobacter chromosomes to Pseudomonas conjugative plasmids via common transposable elements (IS1182 and IS3/IS6 elements) in composite transposons, carrying also other genes involved in guanylurea and biguanides degradation (guuH and bguH). These mobile elements, historically involved in acquisition of antibiotic-resistant genes from the environment before clonal expansion in clinical settings, now threaten to co-select for both metformin-degrading and antibiotic resistance genes in contaminated waters. This represents a global threat for diabetic patients with concurrent infections that should be urgently added in the roadmap of research in the context of One Health.