Strain-specific impacts of probiotics are a significant driver of gut microbiome development in very preterm infants. Nature microbiology The development of the gut microbiome from birth plays important roles in short- and long-term health, but factors influencing preterm gut microbiome development are poorly understood. In the present study, we use metagenomic sequencing to analyse 1,431 longitudinal stool samples from 123 very preterm infants (<32 weeks' gestation) who did not develop intestinal disease or sepsis over a study period of 10 years. During the study period, one cohort had no probiotic exposure whereas two cohorts were given different probiotic products: Infloran (Bifidobacterium bifidum and Lactobacillus acidophilus) or Labinic (B. bifidum, B. longum subsp. infantis and L. acidophilus). Mothers' own milk, breast milk fortifier, antibiotics and probiotics were significantly associated with the gut microbiome, with probiotics being the most significant factor. Probiotics drove microbiome transition into different preterm gut community types (PGCTs), each enriched in a different Bifidobacterium sp. and significantly associated with increased postnatal age. Functional analyses identified stool metabolites associated with PGCTs and, in preterm-derived organoids, sterile faecal supernatants impacted intestinal, organoid monolayer, gene expression in a PGCT-specific manner. The present study identifies specific influencers of gut microbiome development in very preterm infants, some of which overlap with those impacting term infants. The results highlight the importance of strain-specific differences in probiotic products and their impact on host interactions in the preterm gut. 10.1038/s41564-022-01213-w

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections. Science translational medicine Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( and ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with , as well as when dosed orally in an antibiotic-induced infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics. 10.1126/scitranslmed.abj2381

Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases. Nature medicine Fecal microbiota transplantation (FMT) is highly effective against recurrent Clostridioides difficile infection and is considered a promising treatment for other microbiome-related disorders, but a comprehensive understanding of microbial engraftment dynamics is lacking, which prevents informed applications of this therapeutic approach. Here, we performed an integrated shotgun metagenomic systematic meta-analysis of new and publicly available stool microbiomes collected from 226 triads of donors, pre-FMT recipients and post-FMT recipients across eight different disease types. By leveraging improved metagenomic strain-profiling to infer strain sharing, we found that recipients with higher donor strain engraftment were more likely to experience clinical success after FMT (P = 0.017) when evaluated across studies. Considering all cohorts, increased engraftment was noted in individuals receiving FMT from multiple routes (for example, both via capsules and colonoscopy during the same treatment) as well as in antibiotic-treated recipients with infectious diseases compared with antibiotic-naïve patients with noncommunicable diseases. Bacteroidetes and Actinobacteria species (including Bifidobacteria) displayed higher engraftment than Firmicutes except for six under-characterized Firmicutes species. Cross-dataset machine learning predicted the presence or absence of species in the post-FMT recipient at 0.77 average AUROC in leave-one-dataset-out evaluation, and highlighted the relevance of microbial abundance, prevalence and taxonomy to infer post-FMT species presence. By exploring the dynamics of microbiome engraftment after FMT and their association with clinical variables, our study uncovered species-specific engraftment patterns and presented machine learning models able to predict donors that might optimize post-FMT specific microbiome characteristics for disease-targeted FMT protocols. 10.1038/s41591-022-01964-3

The AAA+ ATPase RavA and its binding partner ViaA modulate E. coli aminoglycoside sensitivity through interaction with the inner membrane. Nature communications Enteric bacteria have to adapt to environmental stresses in the human gastrointestinal tract such as acid and nutrient stress, oxygen limitation and exposure to antibiotics. Membrane lipid composition has recently emerged as a key factor for stress adaptation. The E. coli ravA-viaA operon is essential for aminoglycoside bactericidal activity under anaerobiosis but its mechanism of action is unclear. Here we characterise the VWA domain-protein ViaA and its interaction with the AAA+ ATPase RavA, and find that both proteins localise at the inner cell membrane. We demonstrate that RavA and ViaA target specific phospholipids and subsequently identify their lipid-binding sites. We further show that mutations abolishing interaction with lipids restore induced changes in cell membrane morphology and lipid composition. Finally we reveal that these mutations render E. coli gentamicin-resistant under fumarate respiration conditions. Our work thus uncovers a ravA-viaA-based pathway which is mobilised in response to aminoglycosides under anaerobiosis and engaged in cell membrane regulation. 10.1038/s41467-022-32992-9