Maternal activation of the EGFR prevents translocation of gut-residing pathogenic in a model of late-onset neonatal sepsis.

Late-onset sepsis (LOS) is a highly consequential complication of preterm birth and is defined by a positive blood culture obtained after 72 h of age. The causative bacteria can be found in patients' intestinal tracts days before dissemination, and cohort studies suggest reduced LOS risk in breastfed preterm infants through unknown mechanisms. Reduced concentrations of epidermal growth factor (EGF) of maternal origin within the intestinal tract of mice correlated to the translocation of a gut-resident human pathogen , which spreads systemically and caused a rapid, fatal disease in pups.

Persistent metagenomic signatures of early-life hospitalization and antibiotic treatment in the infant gut microbiota and resistome.

Hospitalized preterm infants receive frequent and often prolonged exposures to antibiotics because they are vulnerable to infection. It is not known whether the short-term effects of antibiotics on the preterm infant gut microbiota and resistome persist after discharge from neonatal intensive care units. Here, we use complementary metagenomic, culture-based and machine learning techniques to study the gut microbiota and resistome of antibiotic-exposed preterm infants during and after hospitalization, and we compare these readouts to antibiotic-naive healthy infants sampled synchronously.

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. We exposed the candidate probiotic E.

Semisynthetic Analogues of Anhydrotetracycline as Inhibitors of Tetracycline Destructase Enzymes.

The synthesis and biological evaluation of semisynthetic anhydrotetracycline analogues as small molecule inhibitors of tetracycline-inactivating enzymes are reported. Inhibitor potency was found to vary as a function of enzyme (major) and substrate-inhibitor pair (minor), and anhydrotetracycline analogue stability to enzymatic and nonenzymatic degradation in solution contributes to their ability to rescue tetracycline activity in whole cell Escherichia coli expressing tetracycline destructase enzymes. Taken collectively, these results provide the framework for the rational design of next-generation inhibitor libraries en route to a viable and proactive adjuvant approach to combat the enzymatic degradation of tetracycline antibiotics.

Multiscale Evolutionary Dynamics of Host-Associated Microbiomes.

The composite members of the microbiota face a range of selective pressures and must adapt to persist in the host. We highlight recent work characterizing the evolution and transfer of genetic information across nested scales of host-associated microbiota, which enable resilience to biotic and abiotic perturbations. At the strain level, we consider the preservation and diversification of adaptive information in progeny lineages.

Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes.

Although tetracyclines are an important class of antibiotics for use in agriculture and the clinic, their efficacy is threatened by increasing resistance. Resistance to tetracyclines can occur through efflux, ribosomal protection, or enzymatic inactivation. Surprisingly, tetracycline enzymatic inactivation has remained largely unexplored, despite providing the distinct advantage of antibiotic clearance.

Next-generation approaches to understand and combat the antibiotic resistome.

Antibiotic resistance is a natural feature of diverse microbial ecosystems. Although recent studies of the antibiotic resistome have highlighted barriers to the horizontal transfer of antibiotic resistance genes between habitats, the rapid global spread of genes that confer resistance to carbapenem, colistin and quinolone antibiotics illustrates the dire clinical and societal consequences of such events. Over time, the study of antibiotic resistance has grown from focusing on single pathogenic organisms in axenic culture to studying antibiotic resistance in pathogenic, commensal and environmental bacteria at the level of microbial communities.

Genomic and functional techniques to mine the microbiome for novel antimicrobials and antimicrobial resistance genes.

Microbial communities contain diverse bacteria that play important roles in every environment. Advances in sequencing and computational methodologies over the past decades have illuminated the phylogenetic and functional diversity of microbial communities from diverse habitats. Among the activities encoded in microbiomes are the abilities to synthesize and resist small molecules, yielding antimicrobial activity.

Antibiotic perturbation of the preterm infant gut microbiome and resistome.

The gut microbiota plays important roles in nutrient absorption, immune system development, and pathogen colonization resistance. Perturbations early in life may be detrimental to host health in the short and the long-term. Antibiotics are among the many factors that influence the development of the microbiota.