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"Wright, D."
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Drug combinations: a strategy to extend the life of antibiotics in the 21st century
Antimicrobial resistance threatens a resurgence of life-threatening bacterial infections and the potential demise of many aspects of modern medicine. Despite intensive drug discovery efforts, no new classes of antibiotics have been developed into new medicines for decades, in large part owing to the stringent chemical, biological and pharmacological requisites for effective antibiotic drugs. Combinations of antibiotics and of antibiotics with non-antibiotic activity-enhancing compounds offer a productive strategy to address the widespread emergence of antibiotic-resistant strains. In this Review, we outline a theoretical and practical framework for the development of effective antibiotic combinations.Combinations of antibiotics and of antibiotics with non-antibiotic activity-enhancing compounds offer a productive strategy to address the widespread emergence of antibiotic-resistant strains. In this Review, Tyers and Wright outline a theoretical and practical framework for the development of effective drug combinations.
Journal Article
Antibacterial drug discovery in the resistance era
The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.
Journal Article
All-optical spiking neurosynaptic networks with self-learning capabilities
Software implementations of brain-inspired computing underlie many important computational tasks, from image processing to speech recognition, artificial intelligence and deep learning applications. Yet, unlike real neural tissue, traditional computing architectures physically separate the core computing functions of memory and processing, making fast, efficient and low-energy computing difficult to achieve. To overcome such limitations, an attractive alternative is to design hardware that mimics neurons and synapses. Such hardware, when connected in networks or neuromorphic systems, processes information in a way more analogous to brains. Here we present an all-optical version of such a neurosynaptic system, capable of supervised and unsupervised learning. We exploit wavelength division multiplexing techniques to implement a scalable circuit architecture for photonic neural networks, successfully demonstrating pattern recognition directly in the optical domain. Such photonic neurosynaptic networks promise access to the high speed and high bandwidth inherent to optical systems, thus enabling the direct processing of optical telecommunication and visual data.
An optical version of a brain-inspired neurosynaptic system, using wavelength division multiplexing techniques, is presented that is capable of supervised and unsupervised learning.
Journal Article
Violence, Periodization and Definition of the Cultural Revolution : A Case Study of Two deaths by the Red Guards
\"This book recounts two deaths, the murder of Mr. Wang Jin by 31 Red Guards in the Nanjing Foreign Language School, where the senior author was a young student at the time; and the earlier murder of Mrs. Bian Zhongyun of the Girls School affiliated with the Beijing Normal University in 1966. The book is a history of two small incidents in a massive social injustice and also an attempt to understand the Cultural Revolution (CR) within the framework of modern social movement theory. The book elaborates on the sources of violence in the CR, and the definition and periodization of the CR (that is, what was it, and when did it begin and end?)\"--Back cover.
Book
The antibiotic resistome: the nexus of chemical and genetic diversity
Key Points
The antibiotic resistome is the collection of all the antibiotic resistance genes, including those usually associated with pathogenic bacteria isolated in the clinics, non-pathogenic antibiotic producing bacteria and all other resistance genes.
Many bacterial genomes contain cryptic resistance genes that can confer resistance, but do not seem to have been selected in response to recent exposure to antibiotics. These represent a large reservoir of antibiotic resistance genes.
The antibiotic resistance genes in environmental and other non-pathogenic bacteria share amino-acid sequence similarities and biochemical mechanisms with resistance elements in clinical isolates.
Structural biology and protein biochemistry has revealed that antibiotic resistance has evolved from precursor proteins with other metabolic functions. The powerful selection pressure produced by the use of cytotoxic antimicrobial agents spurs the selection of resistance mechanisms from these precursors.
Antibiotics are ancient, dating back hundreds of millions of years. Resistance is therefore equally ancient, and the number of genes in the resistome is a reflection of the continuous co-evolution of small molecules in natural environments and microbial genomes.
Resistance to antibiotics in microorganisms predates the use of these drugs. This Review examines why antibiotic resistance is inevitable and where it originates from.
Over the millennia, microorganisms have evolved evasion strategies to overcome a myriad of chemical and environmental challenges, including antimicrobial drugs. Even before the first clinical use of antibiotics more than 60 years ago, resistant organisms had been isolated. Moreover, the potential problem of the widespread distribution of antibiotic resistant bacteria was recognized by scientists and healthcare specialists from the initial use of these drugs. Why is resistance inevitable and where does it come from? Understanding the molecular diversity that underlies resistance will inform our use of these drugs and guide efforts to develop new efficacious antibiotics.
Journal Article
Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome
Antibiotic resistance is a global challenge that impacts all pharmaceutically used antibiotics. The origin of the genes associated with this resistance is of significant importance to our understanding of the evolution and dissemination of antibiotic resistance in pathogens. A growing body of evidence implicates environmental organisms as reservoirs of these resistance genes; however, the role of anthropogenic use of antibiotics in the emergence of these genes is controversial. We report a screen of a sample of the culturable microbiome of Lechuguilla Cave, New Mexico, in a region of the cave that has been isolated for over 4 million years. We report that, like surface microbes, these bacteria were highly resistant to antibiotics; some strains were resistant to 14 different commercially available antibiotics. Resistance was detected to a wide range of structurally different antibiotics including daptomycin, an antibiotic of last resort in the treatment of drug resistant Gram-positive pathogens. Enzyme-mediated mechanisms of resistance were also discovered for natural and semi-synthetic macrolide antibiotics via glycosylation and through a kinase-mediated phosphorylation mechanism. Sequencing of the genome of one of the resistant bacteria identified a macrolide kinase encoding gene and characterization of its product revealed it to be related to a known family of kinases circulating in modern drug resistant pathogens. The implications of this study are significant to our understanding of the prevalence of resistance, even in microbiomes isolated from human use of antibiotics. This supports a growing understanding that antibiotic resistance is natural, ancient, and hard wired in the microbial pangenome.
Journal Article