Project description:Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positivebacterial pathogens without detectable resistance. Using biochemical assays,solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C55PP, Lipid II, LipidWTA). Clovibactin uses anunusual hydrophobic interface to tightly wrap aroundpyrophosphate, butbypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups.Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.
Project description:Here, we have used single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq) and spatial transcriptomics to characterize murine cortical OPCs throughout postnatal life. During development, we identify two differentially-localized PDGFRα-positive OPC populations that are transcriptionally and epigenetically distinct. One population (active or actOPCs) is metabolically active and is enriched in white matter. The second (homeostatic or hOPCs) is less active, enriched in grey matter, and predicted to derive from actOPCs. In adulthood, these two groups are transcriptionally but not epigenetically distinct, and relative to developing OPCs are less active metabolically with much less open chromatin. When adult oligodendrogenesis is enhanced following experimental demyelination, adult OPCs do not reacquire a developmental open chromatin state, and the oligodendrogenesis trajectory is distinct from that seen neonatally. These data support a model where two OPC populations subserve distinct postnatal functions, and where neonatal and adult OPC-mediated oligodendrogenesis are fundamentally different.
