Studying proteins through the lens of evolution can help identify conserved features and lineage-specific variants, and potentially, their functions. MolEvolvR (http://jravilab.org/molevolvr) is a web-app that enables researchers to run a general-purpose computational workflow for characterizing the molecular evolution and phylogeny of their proteins of interest. The web-app accepts input in multiple formats: protein/domain sequences, homologous proteins, or domain scans. MolEvolvR returns detailed homolog data, along with dynamic graphical summaries, e.g., MSA, phylogenetic trees, domain architectures, domain proximity networks, phyletic spreads, and co-occurrence patterns across lineages. Thus, MolEvolvR provides a powerful, easy-to-use interface for computational protein characterization.
Sulfur is an indispensable element for proliferation of bacterial pathogens. Prior studies indicated that the human pathogen, Staphylococcus aureus utilizes glutathione (GSH) as a source of nutrient sulfur; however, mechanisms of GSH acquisition are not defined. Here, we identify a previously uncharacterized five-gene locus comprising a putative ABC-transporter and γ–glutamyl transpeptidase (ggt) that promotes S. aureus proliferation in medium supplemented with either reduced or oxidized GSH (GSSG) as the sole source of nutrient sulfur. Based on these phenotypes, we name this transporter the Glutathione import system (GisABCD). We confirm that Ggt is capable of cleaving GSH and GSSG γ–bonds and that this process is required for their use as nutrient sulfur sources. Additionally, we find that the enzyme is cell associated. Bioinformatic analyses reveal that only Staphylococcus species closely related to S. aureus encode GisABCD-Ggt homologues. Homologues are not detected in Staphylococcus epidermidis. Consequently, we establish that GisABCD-Ggt provides a competitive advantage for S. aureus over S. epidermidis in a GSH-dependent manner. Overall, this study describes the discovery of a nutrient sulfur acquisition system in S. aureus that targets GSH and promotes competition against other staphylococci commonly associated with the human microbiota.
Novel small molecule therapies for cystic fibrosis (CF) are showing promising efficacy and becoming more widely available since recent FDA approval. The newest of these is a triple therapy of Elexacaftor-Tezacaftor-Ivacaftor (ETI). Little is known about how these drugs will affect polymicrobial lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF). We analyzed the sputum microbiome and metabolome from pwCF (n=24) before and after TKT therapy using 16S rRNA gene amplicon sequencing and untargeted metabolomics. The lung microbiome diversity, particularly its evenness, was increased (p = 0.044) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes were more similar within an individual than across the sampled population. There were no specific microbial taxa that were different in abundance before and after therapy, but collectively, the log-ratio of anaerobes to pathogens significantly decreased. The sputum metabolome also showed changes due to TKT. Beta-diversity increased after therapy (PERMANOVA F=4.22, p=0.022) and was characterized by greater variation across subjects while on treatment. This significant difference in the metabolome was driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway. Metabolism of the three small molecules that make up TKT was extensive, including previously uncharacterized structural modifications. This study shows that TKT therapy affects both the microbiome and metabolome of airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche spaces for microbial residency in lung mucus as the drug effects take hold, which then leads to changing microbiology.
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