Biology subjects

Dantas, G.

Publications and source records attributed to Dantas, G..

6 recordsLinked to original sources

bioRxiv2024

Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization

Gastrointestinal colonization by Clostridioides difficile is common in healthcare settings and ranges in clinical presentation from asymptomatic carriage to lethal C. difficile infection (CDI). We used a systems biology approach to investigate why patients colonized with C. difficile have a range of outcomes. Microbiota-humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clade 1 lineages and identified commensal Blautia associated with markers of non-pathogenic colonization. Using gnotobiotic mice engrafted with defined human microbiota, we observed strain-specific CDI severity across clade 1 strains. Yet, mice engrafted with a higher diversity community were protected from severe disease across all strains without suppression of C. difficile colonization. These results indicate that when colonization resistance has been breached without overt infection, commensals can attenuate a diversity of virulent strains without inhibiting pathogen colonization, providing insight into determinants of stable C. difficile carriage.

microbiology↗

bioRxiv2024

Quantifying the genomic determinants of fitness in E. coli ST131 using phylodynamics

Antimicrobial resistant pathogens such as Escherichia coli sequence type 131 (ST131) pose a serious threat to public health globally. In the United States, ST131 acquired multiple antimicrobial resistance (AMR) genes and rapidly grew to its current high prevalence in healthcare settings. Notably, this coincided with the introduction and widespread use of antibiotics such as fluoroquinolones, suggesting AMR as the major driver of ST131s expansion. Yet, within ST131, there remains considerable diversity between strains in resistance profiles and their repertoires of virulence factors, stress factors, plasmids, and other accessory elements. Understanding which genomic features contribute to ST131s competitive advantage and their relative effects on population-level fitness therefore poses a considerable challenge. Here we use phylodynamic birth-death models to estimate the relative fitness of different ST131 lineages from bacterial phylogenies. By extending these phylodynamic methods to allow multiple genomic features to shape bacterial fitness, we further quantify the relative contribution of individual AMR genes to ST131s fitness. Our analysis indicates that while many genomic elements, including various AMR genes, virulence factors, and plasmids, have all contributed substantially to ST131s rapid growth, major increases in ST131s fitness are largely attributable to mutations in gyrase A that confer resistance to fluoroquinolones. Author summaryST131 is a pandemic lineage of E. coli that has spread globally and is now responsible for a large percentage of blood and urinary tract infections that cannot be treated with many common antibiotics. While antibiotic resistance has undoubtedly given ST131 a competitive edge, the relative importance of resistance compared with other factors shaping a pathogens growth or transmission potential (i.e. fitness) is often difficult to measure in natural settings. Here, we present a method that allows us to look at the entire spectrum of factors determining a pathogens fitness and estimate the individual contribution of each component to pathogens overall fitness. Our results suggest that resistance to fluoroquinolones, a widely used class of antibiotics, provides ST131 with a disproportionately large fitness advantage relative to many other factors with more moderate fitness effects. Understanding what determines the fitness of ST131 therefore provides insights that can be used to curb the spread of resistance and monitor for emerging lineages with high pandemic potential due to shared fitness enhancing attributes.

evolutionary biology↗

bioRxiv2021

Structural and molecular rationale for the diversification of resistance mediated by the Antibiotic_NAT family

The environmental microbiome harbors a vast repertoire of antibiotic resistance genes (ARGs) which can serve as evolutionary predecessors for ARGs found in pathogenic bacteria, or can be directly mobilized to pathogens in the presence of selection pressures. Thus, ARGs from benign environmental bacteria are an important resource for understanding clinically relevant resistance. Here, we conduct a comprehensive functional analysis of the Antibiotic_NAT family of aminoglycoside acetyltransferases. We determined a pan-family antibiogram of 21 Antibiotic_NAT enzymes, including 8 derived from clinical isolates and 13 from environmental metagenomic samples. We find that environment-derived representatives confer high-level, broad-spectrum resistance, including against the atypical aminoglycoside apramycin, and that a metagenome-derived gene likely is ancestral to an AAC(3) gene found in clinical isolates. Through crystallographic analysis, we rationalize the molecular basis for diversification of substrate specificity across the family. This work provides critical data on the molecular mechanism underpinning resistance to established and emergent aminoglycoside antibiotics and broadens our understanding of ARGs in the environment.

microbiology↗

bioRxiv2021

Multi-omics investigation of Clostridioides difficile-colonized patients reveals protective commensal carbohydrate metabolism

Clostridioides difficile infection (CDI) imposes a substantial burden on the health care system in the United States. Understanding the biological basis for the spectrum of C. difficile-related disease manifestations is imperative to improving treatment and prevention of CDI. Here, we investigate the correlates of asymptomatic C. difficile colonization using a multi-omics approach, comparing the fecal microbiome and metabolome profiles of patients with CDI versus asymptomatically-colonized patients. We find that microbiomes of asymptomatic patients are significantly enriched for species in the class Clostridia relative to those of symptomatic patients. Asymptomatic patient microbiomes were enriched with fucose, rhamnose, and sucrose degradation pathways relative to CDI patient microbiomes. Fecal metabolomics corroborates this result: we identify carbohydrate compounds enriched in asymptomatic patients relative to CDI patients, and correlated with a number of commensal Clostridia. Further, we reveal that across C. difficile isolates, the carbohydrates rhamnose and lactulose do not serve as robust growth substrates in vitro, corroborating their enriched detection in our metagenomic and metabolite profiling of asymptomatic individuals. We conclude that in asymptomatically-colonized individuals, carbohydrate metabolism by other commensal Clostridia may prevent CDI by inhibiting C. difficile proliferation. These insights into C. difficile colonization and putative commensal competition suggest novel avenues to develop probiotic or prebiotic therapeutics against CDI.

microbiology↗

bioRxiv2021

Pathogenic potential in catheter associated Escherichia coli is associated with separable biofilm and virulence gene determinants

Urinary catheterization facilitates Escherichia coli colonization of the urinary tract and increases infection risk. While specific pathotypes are well-recognized for some E. coli infections, it is unclear whether strain-specific characteristics among E. coli are associated with infection risk in catheterized patients. Here we used comparative genomics and a simulated catheter biofilm model to compare strains associated with catheter-associated urinary tract infection (CAUTI) and catheter-associated asymptomatic bacteriuria (CAASB). CAUTI was associated with a phylotype B2 sub-clade dominated by the multidrug resistant ST131 lineage, while CAASB isolates were genetically more diverse. Catheter-associated biofilm formation was widespread but quantitatively variable among isolates. Network community analysis resolved distinct groups of genes associated with infection or biofilm formation, with iron acquisition-associated genes prominent throughout. Using a reporter construct and targeted mutagenesis, we detected a biofilm phenotype for the ferric citrate transport (Fec) system, the most prominent correlate of high catheter biofilm formation in these patients. In mixed cultures, catheter biofilms formed by some CAASB strains suppressed catheter colonization by ST131 CAUTI isolates. These results are consistent with a paradigm in which catheter biofilm-associated genes increase infection risk in strains with a high pathogenic potential and decrease infection risk through niche exclusion in strains with low pathogenic potential.

microbiology↗

bioRxiv2018

Adaptive strategies of the candidate probiotic E. coli Nissle in the mammalian gut

Probiotics are living microorganisms that are increasingly used as gastrointestinal therapeutics by virtue of their innate or engineered genetic function. Unlike abiotic therapeutics, probiotics can replicate in their intended site, subjecting their genomes and therapeutic properties to natural selection. By exposing the candidate probiotic E. coli Nissle (EcN) to the mouse gastrointestinal tract over several weeks, we uncovered the consequences of gut transit, inter-species competition, antibiotic pressure, and engineered genetic function on the processes under selective pressure during both within-genome and horizontal evolutionary modes. We then show the utility of EcN as a chassis for engineered function by achieving the highest reported reduction in serum phenylalanine levels in a mouse model of phenylketonuria using an engineered probiotic. Collectively, we demonstrate a generalizable pipeline which can be applied to other probiotic strains to better understand their safety and engineering potential.

evolutionary biology↗