The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences aff ect everybody in the world. Similarities with climate change are evident. Many eff orts have been made to describe the many diff erent facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to eff ective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment.A ntibiotic resistance is an increasing crisis as both the range of microbial antibiotic resistance in clinical settings expands and the pipeline for development of new antibiotics contracts (1). This problem is compounded by the global genomic scope of the antibiotic resistome, such that antibiotic resistance spans a continuum from genes in pathogens found in the clinic to those of benign environmental microbes along with their proto-resistance gene progenitors (2, 3). The recent emergence of New Delhi metallo-ß-lactamase (NDM-1) in Gram-negative organisms (4), which can hydrolyze all ␤-lactams with the exception of monobactams, illustrates the capacity of new antibiotic resistance genes to emerge rapidly from as-yet-undetermined reservoirs. Surveys of genes originating from both clinical and environmental sources (microbes and metagenomes) will provide increasing insight into these reservoirs and offer predictive capacity for the emergence and epidemiology of antibiotic resistance.The increasing opportunity to prepare a broader and comprehensive antibiotic resistance gene census is facilitated by the power and falling costs of next-generation DNA sequencing. For example, whole-genome sequencing (WGS) is being increasingly used to examine new antibiotic-resistant isolates discovered in clinical settings (5). Additionally, culture-independent metagenomic surveys are adding tremendously to the pool of known genes and their distribution outside clinical settings (6, 7). These approaches have the advantage of providing a rapid survey of the antibiotic resistome of new strains, the discovery of newly emergent antibiotic resistance genes, the epidemiology of antibiotic resistance genes, and the horizontal gene transfer (HGT) of known antibiotic resistance genes through plasmids and transposable elements. However, despite the existence of tools for general annotation of prokaryotic genomes (see, e.g., reference 8), prediction of an antibiotic resista...

The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases by the emergence of resistant microbes. This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics. Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.

Microbial resistance to antibiotics currently spans all known classes of natural and synthetic compounds. It has not only hindered our treatment of infections but also dramatically reshaped drug discovery, yet its origins have not been systematically studied. Soil-dwelling bacteria produce and encounter a myriad of antibiotics, evolving corresponding sensing and evading strategies. They are a reservoir of resistance determinants that can be mobilized into the microbial community. Study of this reservoir could provide an early warning system for future clinically relevant antibiotic resistance mechanisms.

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.

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