Biology subjects

Rolain, J.-M.

Publications and source records attributed to Rolain, J.-M..

5 recordsLinked to original sources

bioRxiv2026

Bacterial NDH-1 is a key gut target of metformin mediating its antidiabetic effects

Metformin is the first-line therapy for type 2 diabetes, yet the mechanisms underlying its glucose-lowering effects remain incompletely understood. Increasing evidence implicates gut microbiota as an important mediator of metformin action, but the bacterial targets of the drug remain poorly defined. Here, we identify bacterial NADH oxidoreductase (NDH-1), the homolog of mitochondrial complex I, as a key target of metformin. Metformin inhibited bacterial growth at millimolar concentrations and, at subinhibitory concentrations, markedly impaired carbohydrate fermentation in Escherichia coli and other NDH-1-containing bacteria. Supplementation with nicotinic acid and Mg2+; restored fermentation, whereas pyruvate bypassed the metabolic defect, implicating impaired NAD+; regeneration and disruption of metabolism upstream of pyruvate formation. Genetic analysis further established NDH-1 dependence: metformin failed to inhibit fermentation in an E. coli delta-nuoF mutant lacking functional NDH-1 but retained activity in an NDH-2-deficient delta-ndh strain. Molecular docking predicted metformin binding within the NDH-1 quinone-binding region, proximal to conserved residues involved in quinone reduction. Consistent with this mechanism, Staphylococcus aureus, which lacks NDH-1, was not affected in carbohydrate fermentation, while several gut-associated probiotic and short-chain fatty acid-producing bacteria, including Lactobacillus, Bifidobacterium, and Akkermansia muciniphila, lacked detectable NDH-1 homologs, suggesting intrinsic resistance to this metabolic effect of metformin. These findings identify bacterial NDH-1 as a metabolic target of metformin and provide a mechanistic framework for its effects on the gut microbiota. Selective inhibition of NDH-1-dependent bacteria could alter microbial substrate utilization and ecological interactions in the intestine, potentially contributing to the microbiome-mediated component of metformin's antidiabetic effects.

microbiology↗

bioRxiv2025

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

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.

microbiology↗

bioRxiv2021

Small and equipped: the rich repertoire of antibiotic resistance genes in Candidate Phyla Radiation genomes

Microbes belonging to Candidate Phyla Radiation (CPR) have joined the tree of life as a new unique branch, thanks to the intensive application of metagenomics and advances of sequencing technologies. Despite their ultra-small size, reduced genome and metabolic pathways which mainly depend on symbiotic/exo-parasitic relationship with their bacterial host, CPR microbes are abundant and ubiquitous in almost all environments and are consequently survivors in highly competitive circumstances within microbial communities. They have been eventually identified by 16S rRNA analysis and represent more than 26% of microbial diversity. CPR microbes were able to survive in this context, although their defence mechanisms and phenotypic characteristic remain, however, poorly explored. Here, we conducted a thorough in-silico analysis on 4,062 CPR genomes to test whether these ultrasmall microorganisms might encode for antibiotic resistance (AR)-like enzymes. We used an adapted AR screening criteria with an exhaustive consensus database and complementary steps conferring their resistance functions. We conclude by reporting the surprising discovery of rich reservoir of divergent AR-like genes (n= 30,545 HITs, mean=7.5 HITs/genome [0-41] encoding for 89 AR enzymes, distributed across the 13 CPR phyla, and associated with 14 different chemical classes of antimicrobials. However, most HITs found (93.6%) were linked to glycopeptide, beta-lactams, macrolide-lincosamide-streptogramin, tetracycline and aminoglycoside resistance. Moreover, a distinct AR profile was discerned between the microgenomates group and Candidatus Parcubacteria, and between each of them and other CPR phyla. CPR cells seem to be active players during microbial competitive interactions and are well-equipped for the microbial combat in different habitats, supporting their natural survival/persistence and continued existence.

microbiology↗

bioRxiv2019

Massive analysis of 64’628 bacterial genomes to decipher a water reservoir and origin of mobile colistin resistance (mcr) gene variants: is there another role for this family of enzymes?

Since 2015, new worrying colistin resistance mechanism, mediated by mcr-1 gene has been reported worldwide along with eight newly described variants (mcr-2 to mcr-9) but their source(s) and reservoir(s) remain largely unexplored. Here, we conducted a massive bioinformatic analysis of 64628 downloaded bacterial genomes to investigate the reservoir and origin of these mcr variants. We identified a total of 6651 significant positive hits (aa sequence coverage > 90 % and similarity >50%) with the nine MCR variants from these genomes that include 39 bacterial genera and more than 1050 species. Although these variants could be identified in bacteria from human and animal sources, we found plenty MCR variants in unsuspected bacteria from environmental origin, especially from water sources. The ubiquitous presence of mcr variants in bacteria from water likely suggests another role in the biosphere of these enzymes as an unknown defense system against natural antimicrobial peptides and/or bacteriophage predation.

genomics↗

bioRxiv2019

Paradoxical β-lactamase activity of archaeal encoding enzymes

{beta}-lactams targeting the bacterial cell wall are not active on archaea. Here, we figure out that annotation of genes as {beta}-lactamase in Archeae on the basis of homologous genes, initially annotated {beta}-lactamases, is a remnant of the identification of the original activities of this group of enzymes, which in fact, have multiple functions including nuclease, ribonuclease, {beta}-lactamase, or glyoxalase; which may specialized over time. We expressed a class B {beta}-lactamase enzyme from Methanosarcina barkeri that digest penicillin G. Moreover, while a weak glyoxalase activity was detected, a significant ribonuclease activity on bacterial and synthetic RNAs was demonstrated. The {beta}-lactamase activity was inhibited by a {beta}-lactamase inhibitor (sulbactam), but its RNAse activity was not. This gene appears to has been transferred to the Flavobacteriaceae group including Elizabethkingia genus in which the expressed gene shows a more specialized activity toward resistance to tienanmicin but no glyoxalase activity. The expressed class C-like {beta}-lactamase gene, also from Methanosarcina sp., shows also hydrolysis activity and was more closely related to DD-peptidase enzymes than known bacterial class C {beta}-lactamases. Our findings highlight the requalification needness of annotated enzymes as {beta}-lactamases and the specification overtime of multipotent enzymes in different ways in Archaea and bacteria.

microbiology↗