资源环境科技发展态势分析平台

Bacteria are under immense evolutionary pressure from their viral invaders-bacteriophages. Bacteria have evolved numerous immune mechanisms, both innate and adaptive, to cope with this pressure. The discovery and exploitation of CRISPR-Cas systems have stimulated a resurgence in the identification and characterization of anti-phage mechanisms. Bacteriophages use an extensive battery of counter-defence strategies to co-exist in the presence of these diverse phage defence mechanisms. Understanding the dynamics of the interactions between these microorganisms has implications for phage-based therapies, microbial ecology and evolution, and the development of new biotechnological tools. Here we review the spectrum of anti-phage systems and highlight their evasion by bacteriophages.

The fossil record of mammaliaforms (mammals and their closest relatives) of the Mesozoic era from the southern supercontinent Gondwana is far less extensive than that from its northern counterpart, Laurasia(1,2). Among Mesozoic mammaliaforms, Gondwanatheria is one of the most poorly known clades, previously represented by only a single cranium and isolated jaws and teeth(1-5). As a result, the anatomy, palaeobiology and phylogenetic relationships of gondwanatherians remain unclear. Here we report the discovery of an articulated and very well-preserved skeleton of a gondwanatherian of the latest age (72.1-66 million years ago) of the Cretaceous period from Madagascar that we assign to a new genus and species, Adalatherium hui. To our knowledge, the specimen is the most complete skeleton of a Gondwanan Mesozoic mammaliaform that has been found, and includes the only postcranial material and ascending ramus of the dentary known for any gondwanatherian. A phylogenetic analysis including the new taxon recovers Gondwanatheria as the sister group to Multituberculata. The skeleton, which represents one of the largest of the Gondwanan Mesozoic mammaliaforms, is particularly notable for exhibiting many unique features in combination with features that are convergent on those of therian mammals. This uniqueness is consistent with a lineage history for A. hui of isolation on Madagascar for more than 20 million years.

Adalatherium hui, a newly discovered gondwanatherian mammal from Madagascar dated to near the end of the Cretaceous period, shows features consistent with a long evolutionary trajectory of isolation in an insular environment.

A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)(1-4). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (M-pro) of SARS-CoV-2: M-pro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2(5,6). We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M-pro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of M-pro. Six of these compounds inhibited M-pro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 mu M. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.

Skeletal inclusions in approximately 99-million-year-old amber from northern Myanmar provide unprecedented insights into the soft tissue and skeletal anatomy of minute fauna, which are not typically preserved in other depositional environments(1-3). Among a diversity of vertebrates, seven specimens that preserve the skeletal remains of enantiornithine birds have previously been described(1,4-8), all of which (including at least one seemingly mature specimen) are smaller than specimens recovered from lithic materials. Here we describe an exceptionally well-preserved and diminutive bird-like skull that documents a new species, which we name Oculudentavis khaungraae gen. et sp. nov. The find appears to represent the smallest known dinosaur of the Mesozoic era, rivalling the bee hummingbird (Mellisuga helenae)-the smallest living bird-in size. The O. khaungraae specimen preserves features that hint at miniaturization constraints, including a unique pattern of cranial fusion and an autapomorphic ocular morphology(9) that resembles the eyes of lizards. The conically arranged scleral ossicles define a small pupil, indicative of diurnal activity. Miniaturization most commonly arises in isolated environments, and the diminutive size of Oculudentavis is therefore consistent with previous suggestions that this amber formed on an island within the Trans-Tethyan arc(10). The size and morphology of this species suggest a previously unknown bauplan, and a previously undetected ecology. This discovery highlights the potential of amber deposits to reveal the lowest limits of vertebrate body size.

Addressing the ongoing antibiotic crisis requires the discovery of compounds with novel mechanisms of action that are capable of treating drug-resistant infections(1). Many antibiotics are sourced from specialized metabolites produced by bacteria, particularly those of the Actinomycetes family(2). Although actinomycete extracts have traditionally been screened using activity-based platforms, this approach has become unfavourable owing to the frequent rediscovery of known compounds. Genome sequencing of actinomycetes reveals an untapped reservoir of biosynthetic gene clusters, but prioritization is required to predict which gene clusters may yield promising new chemical matter(2). Here we make use of the phylogeny of biosynthetic genes along with the lack of known resistance determinants to predict divergent members of the glycopeptide family of antibiotics that are likely to possess new biological activities. Using these predictions, we uncovered two members of a new functional class of glycopeptide antibiotics-the known glycopeptide antibiotic complestatin and a newly discovered compound we call corbomycin-that have a novel mode of action. We show that by binding to peptidoglycan, complestatin and corbomycin block the action of autolysins-essential peptidoglycan hydrolases that are required for remodelling of the cell wall during growth. Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection.

The glycopeptide antibiotic-related compounds complestatin and corbomycin function by binding to peptidoglycan and blocking the action of autolysins-peptidoglycan hydrolase enzymes that remodel the cell wall during growth.