Rooted in the mechanism of action of antibiotics and subject to bacterial evolution, antibiotic resistance is difficult and perhaps impossible to overcome. Nevertheless, strategies can be used to ...minimize the emergence and impact of resistance. Antibiotic adjuvants offer one such approach. These are compounds that have little or no antibiotic activity themselves but act to block resistance or otherwise enhance antibiotic action. Antibiotic adjuvants are therefore delivered in combination with antibiotics and can be divided into two groups: Class I agents that act on the pathogen, and Class II agents that act on the host. Adjuvants offer a means to both suppress the emergence of resistance and rescue the activity of existing drugs, offering an orthogonal strategy complimentary to new antibiotic discovery Video Abstract
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.
The emergence of resistance to all classes of antibiotics in previously susceptible bacterial pathogens is a major challenge to infectious disease medicine. The origin of the genes associated with ...resistance has long been a mystery. There is a growing body of evidence that is demonstrating that environmental microbes are highly drug resistant. The genes that make up this environmental resistome have the potential to be transferred to pathogens and indeed there is some evidence that at least some clinically relevant resistance genes have originated in environmental microbes. Understanding the extent of the environmental resistome and its mobilization into pathogenic bacteria is essential for the management and discovery of antibiotics.
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.
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.
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.
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.
Over the past decade, resistance to antibiotics has emerged as a crisis of global proportion. Microbes resistant to many and even all clinically approved antibiotics are increasingly common and ...easily spread across continents. At the same time there are fewer new antibiotic drugs coming to market. We are reaching a point where we are no longer able to confidently treat a growing number of bacterial infections. The molecular mechanisms of drug resistance provide the essential knowledge on new drug development and clinical use. These mechanisms include enzyme catalyzed antibiotic modifications, bypass of antibiotic targets and active efflux of drugs from the cell. Understanding the chemical rationale and underpinnings of resistance is an essential component of our response to this clinical challenge.
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