Biology subjects

Chevrette, M. G.

Publications and source records attributed to Chevrette, M. G..

10 recordsLinked to original sources

bioRxiv2026

Integrating targeted genome mining and structure-guided modeling reveals unexplored 7-deazapurine-containing pathways

7-deazapurines are nucleoside analogs that play key roles in nucleic acid modification and can serve as building blocks for diverse, bioactive secondary metabolites. Despite their biological significance, their biosynthetic diversity, distribution, and enzymatic determinants of structural diversification remain poorly understood. Here, we leverage large-scale targeted genome mining, phylogenetic, and network analysis to explore 7-deazapurine-containing pathways across [~]2 million bacterial genomes. We identified over 900 candidate biosynthetic gene clusters (BGCs), grouped into more than 100 families, most of which remain uncharacterized. These GATOR-GC-predicted BGCs were predominantly found in Streptomyces. We then examined enzyme-substrate interactions in three representative pathways: (i) peptidyl-deazapurines, (ii) huimycin, and (iii) dapiramicin A. Molecular docking and molecular dynamics (MD) simulations recapitulated known enzyme-substrate interactions and highlighted candidate catalytic residues governing amide bond formation, methylation, and glycosylation. Using this genome- and structure-guided framework, we identified a candidate BGC for dapiramicin A and proposed tailoring steps, including scaffold methylation and deoxy-sugar formation. These findings expand the known diversity of 7-deazapurine-containing BGCs and demonstrate how integrating genome mining with structural modeling can link BGCs to chemical function, providing a foundation for discovering and characterizing 7-deazapurine-containing secondary metabolites. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/718813v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@c00feforg.highwire.dtl.DTLVardef@156468forg.highwire.dtl.DTLVardef@1326e90org.highwire.dtl.DTLVardef@1f8d57b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Community Curation of Microbial Metabolites Enables Biological Insights of Metabolomics Data

Microbial metabolites play a critical role in regulating ecosystems, including the human body and its microbiota. However, understanding the physiologically relevant role of these molecules, especially through liquid chromatography tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomics, poses significant challenges and often requires manual parsing of a large amount of literature, databases, and webpages. To address this gap, we established the Collaborative Microbial Metabolite Center knowledgebase (CMMC-KB), a platform that fosters collaborative efforts within the scientific community to curate knowledge about microbial metabolites. The CMMC-KB aims to collect comprehensive information about microbial molecules originating from microbial biosynthesis, drug metabolism, exposure-related molecules, food, host-derived molecules, and, whenever available, their known activities. Molecules from other sources, including host-produced, dietary, and pharmaceutical compounds, are also included. By enabling direct integration of this knowledgebase with downstream analytical tools, including molecular networking, we can deepen insights into microbiota and their metabolites, ultimately advancing our understanding of microbial ecosystems.

bioinformatics↗

bioRxiv2026

Nematicidal indole oxazoles and chemoattractants from soil bacteria

Ecological interactions between bacteria and nematodes in many environments provide a basis for the prediction that diverse bacteria produce anti-nematode compounds. The discovery of microbial secondary metabolites with broad-spectrum nematostatic or nematicidal properties can be hastened by drug screening approaches that include several nematode species and phenotypes. We cultured a collection of 22 soil-derived bacterial isolates that carry in their genomes putative pathways for production of unknown secondary metabolites. Isolates were cultured in various media to enhance natural product diversity and yield, and we evaluated culture filtrates for activity against two evolutionarily distinct nematode species: Clade V free-living nematode Caenorhabditis elegans and Clade III mammalian parasitic nematodes in the genus Brugia. Partitioned extracts from Pseudomonas sp. strain TE4607 stunted C. elegans development and caused motility defects in both blood-circulating larval and adult stages of Brugia. The primary active compound was identified as labradorin 1, an indole with known antibacterial and anticancer properties that had not been previously described as affecting nematodes. Notably, filtrates of Pseudomonas sp. TE4607 cultures attracted free-living nematodes in sensory assays, adding to evidence that certain Pseudomonas species modulate the behavior of free-living nematodes. These findings underscore the need to further explore the link between nematode sensory responses and whole-organism effects of microbial metabolites, with potential applications in anthelmintic discovery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/700618v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1909e29org.highwire.dtl.DTLVardef@17f9badorg.highwire.dtl.DTLVardef@c59d79org.highwire.dtl.DTLVardef@1e5abbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Skin lipid chemistry influences host-microbiome-pathogen interactions in snake fungal disease (ophidiomycosis)

Within host-microbiome-pathogen systems, the host chemical microenvironment is often overlooked despite its inherent role in host physiology. We used a multifaceted experimental approach encompassing culture-dependent and independent methods, metagenomic and genomic data, and deep neural network modeling to assess the impact of host skin lipid chemistry and the bacterial microbiome on the growth of Ophidiomyces ophidiicola (ophidiomycosis, snake fungal disease). Results suggest that host skin lipid chemistry (e.g., oleic acid, squalene) and bacteria isolated from wild snake skins (e.g., Chryseobacterium sp. and Stenotrophomonas maltophilia) suppress O. ophidiicola growth. Notably, the O. ophidiicola genome contains biosynthetic gene clusters (BGCs) that encode metabolites that may suppress host lipid production, facilitating fungal pathogenicity. The contrastive deep neural network produced a near-perfect alignment of snake skin lipid and microbiome profiles for both individual snakes and disease states. BGCs from bacterial genomes isolated from snake skin overlap with metagenome profiles from wild snakes and correlate with disease state. We highlight antifungal activity found in the diverse lipid milieu of snake skin and bacterial-fungal interactions (BFIs) that structure the skin microbiome. Our results illustrate a strong relationship among a fungal pathogen, the microbiome, and host skin lipid chemistry.

microbiology↗

bioRxiv2025

Targeted genome mining with GATOR-GC maps the evolutionary landscape of biosynthetic diversity

Gene clusters, groups of physically adjacent genes that work collectively, are pivotal to bacterial fitness and valuable in biotechnology and medicine. While various genome mining tools can identify and characterize gene clusters, they often overlook their evolutionary diversity, a crucial factor in revealing novel cluster functions and applications. To address this gap, we developed GATOR-GC, a targeted genome mining tool that enables comprehensive and flexible exploration of gene clusters in a single execution. We show that GATOR-GC identified a diversity of over 4 million gene clusters similar to experimentally validated biosynthetic gene clusters (BGCs) that other tools fail to detect. To highlight the utility of GATOR-GC, we identified previously uncharacterized co-occurring conserved genes potentially involved in mycosporine-like amino acid biosynthesis and mapped the taxonomic and evolutionary patterns of genomic islands that modify DNA with 7-deazapurines. Additionally, with its proximity-weighted similarity scoring, GATOR-GC successfully differentiated BGCs of the FK-family of metabolites (e.g., rapamycin, FK506/520) according to their chemistries. We anticipate GATOR-GC will be a valuable tool to assess gene cluster diversity for targeted, exploratory, and flexible genome mining. GATOR-GC is available at https://github.com/chevrettelab/gator-gc. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/639861v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@6bf054org.highwire.dtl.DTLVardef@6f3eeaorg.highwire.dtl.DTLVardef@18ba201org.highwire.dtl.DTLVardef@3928dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

PARAS: high-accuracy machine-learning of substrate specificities in nonribosomal peptide synthetases

Nonribosomal peptides are diverse natural products with important applications in medicine and agriculture. Bacterial and fungal genomes contain thousands of nonribosomal peptide biosynthetic gene clusters (BGCs) of unknown function, providing a promising resource for peptide discovery. Core structural features of such peptides can be inferred by predicting the substrate(s) of adenylation (A) domains in nonribosomal peptide synthetases (NRPSs). However, existing approaches to A domain prediction rely on limited datasets and often struggle with domains selecting large substrates or from less-studied taxa. Here, we systematically curate and computationally analyse 3,653 A domains and present two high-accuracy specificity predictors, PARAS and PARASECT. A type of A domain with unusually high L-tryptophan specificity was identified through the application of PARAS, and intact protein mass spectrometry to the corresponding NRPS showed it to direct the production of tryptopeptin-related metabolites in Streptomyces species. Together, these technologies will accelerate the characterisation of novel NRPSs and their metabolic products. PARAS and PARASECT are available at https://paras.bioinformatics.nl. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/631717v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@8e48aaorg.highwire.dtl.DTLVardef@144c78dorg.highwire.dtl.DTLVardef@890c11org.highwire.dtl.DTLVardef@1776de9_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

Characterizing constitutive promoters across the Proteobacteria

Although research on promoters has spanned decades, the precise prediction of promoter activity from DNA sequence remains a challenge even in model organisms. Recent literature has identified important differences in the core sequence of {sigma}70 promoters across classes of Proteobacteria as well as a lack of transferability when promoters are moved from host to host. Currently, there is a need for synthetic constitutive promoters spanning a range of expression levels in species outside of Escherichia coli. Additionally, characterization data defining behavior of the same promoter across multiple species would be extremely valuable to the field. Here, we analyzed promoter activity in three classes of Proteobacteria, which enabled us to better understand the sequence elements correlated with a strong promoter in different hosts. In doing so, we identified and characterized constitutive promoters spanning a range of expression in these species for community use and described the portability of a subset of these promoters as they were moved between hosts. These promoter libraries have broad applications as predictable genetic tools to control gene expression in diverse species (1-3). This work adds to the toolkit for gene expression in non-model bacteria and is a step towards the larger goal of accurate promoter prediction in a given host from a de novo sequence.

synthetic biology↗

bioRxiv2020

Long-term cellulose enrichment selects for highly cellulolytic consortia and competition for public goods

The complexity of microbial communities hinders our understanding of how microbial diversity and microbe-microbe interactions impact community functions. Here, using six independent communities originating from the refuse dumps of leaf-cutter ants and enriched using the plant polymer cellulose as the sole source of carbon, we examine how changes in bacterial diversity and interactions impact plant biomass decomposition. Over up to 60 serial transfers ([~]8 months), cellulolytic ability increased then stabilized in four enrichment lines and was variable in two lines. Bacterial community characterization using 16S rRNA gene amplicon sequencing showed community succession differed between the highly cellulolytic and variably cellulolytic enrichment lines. Metagenomic and metatranscriptomic analyses revealed that Cellvibrio and/or Cellulomonas dominated each enrichment line and produced the majority of cellulase enzymes, while diverse taxa were retained within these communities over the duration of transfers. Interestingly, the less cellulolytic communities had a higher diversity of organisms competing for the cellulose breakdown product cellobiose, suggesting that cheating slowed cellulose degradation. In addition, we found competitive exclusion as an important factor shaping all the communities, with the mutual exclusion of specific cellulolytic taxa within individual enrichment lines and the high expression of genes associated with the production of antagonistic compounds. Our results provide insights into how microbial diversity and competition affect the stability and function of cellulose-degrading communities. ImportanceMicrobial communities are a key driver of the carbon cycle through the breakdown of complex polysaccharides in diverse environments including soil, marine systems, and the mammalian gut.However, due to the complexity of these communities, the species-species interactions that impact community structure and ultimately shape the rate of decomposition are difficult to define. Here we performed serial enrichment on cellulose using communities inoculated from leaf-cutter ant refuse dumps, a cellulose-rich environment. By concurrently tracking cellulolytic ability and community composition and through metagenomic and metatranscriptomic sequencing, we analyzed the ecological dynamics of the enrichment lines. Our data suggest that antagonism is prevalent in these communities and that competition for soluble sugars may slow degradation and lead to community instability. Together, these results help reveal the relationships between competition and polysaccharide decomposition, with implications in diverse areas ranging from microbial community ecology to cellulosic biofuels production.

microbiology↗

bioRxiv2019

Biogeography and Microscale Diversity Shape the Biosynthetic Potential of Fungus-growing Ant-associated Pseudonocardia

The geographic and phylogenetic scale of ecologically relevant microbial diversity is still poorly understood. Using a model mutualism, fungus-growing ants and their defensive bacterial associate Pseudonocardia, we analyzed genetic diversity and biosynthetic potential in 46 strains isolated from ant colonies in a 20km transect near Barro Colorado Island in Panama. Despite an average pairwise core genome similarity of greater than 99%, population genomic analysis revealed several distinct bacterial populations matching ant host geographic distribution. We identified both genetic diversity signatures and divergent genes distinct to each lineage. We also identify natural product biosynthesis clusters specific to isolation locations. These geographic patterns were observable despite the populations living in close proximity to each other and provides evidence of ongoing genetic exchange. Our results add to the growing body of literature suggesting that variation in traits of interest can be found at extremely fine phylogenetic scales.

microbiology↗

bioRxiv2018

Bacterial competition mediated by siderophore production among the human nasal microbiota

Resources available in the human nasal cavity are limited. Therefore, to successfully colonize the nasal cavity, bacteria must compete for scarce nutrients. Competition may occur directly through interference (e.g., antibiotics) or indirectly by nutrient sequestration. To investigate the nature of nasal bacterial competition, we performed co-culture inhibition assays between nasal Actinobacteria and Staphylococcus spp. We found that Staphylococcus epidermidis isolates were sensitive to growth inhibition by Actinobacteria but Staphylococcus aureus isolates were resistant to inhibition. Among Actinobacteria, we observed that Corynebacterium spp. were variable in their ability to inhibit S. epidermidis. We sequenced the genomes of ten Corynebacterium spp. isolates, including three Corynebacterium propinquum that strongly inhibited S. epidermidis and seven other Corynebacterium spp. isolates that only weakly inhibited S. epidermidis. Using a comparative genomics approach, we found that the C. propinquum genomes were enriched in genes for iron acquisition and encoded a biosynthetic gene cluster (BGC) for siderophore production, absent in the non-inhibitory Corynebacterium spp. genomes. Using a chromeazurol S assay, we confirmed that C. propinquum produced siderophores. We demonstrated that iron supplementation rescued S. epidermidis from inhibition by C. propinquum, suggesting that inhibition was due to iron restriction through siderophore production. Using comparative metabolomics, we identified the siderophore produced by C. propinquum as dehydroxynocardamine. Finally, we confirmed that the dehydroxynocardamine BGC is expressed in vivo by analyzing human nasal metatranscriptomes from the NIH Human Microbiome Project.\n\nTogether, our results suggest that bacteria produce siderophores to compete for limited available iron in the nasal cavity and improve their fitness.\n\nIMPORTANCEWithin the nasal cavity, interference competition through antimicrobial production is prevalent. For instance, nasal Staphylococcus spp. strains can inhibit the growth of other bacteria through the production of nonribosomal peptides and ribosomally synthesized and post-translationally modified peptides. In contrast, bacteria engaging in exploitation competition modify the external environment to prevent competitors from growing, usually by depleting access to essential nutrients. As the nasal cavity is a nutrient limited environment, we hypothesized that exploitation competition occurs in this system. We determined that Corynebacterium propinquum produces an iron-chelating siderophore and is able to use this molecule to sequester iron and inhibit the growth of Staphylococcus epidermidis. Further, we found that the genes required for siderophore production are expressed in vivo. Thus, though siderophore production by bacteria is often considered a virulence trait, our work indicates that bacteria may produce siderophores to compete for limited iron in the human nasal cavity.

microbiology↗