Influence of Humans on Evolution and Mobilization of Environmental Antibiotic Resistome

The clinical failure of antimicrobial drugs that were previously effective in controlling infectious disease is a tragedy of increasing magnitude that gravely affects human health. This resistance by pathogens is often the endpoint of an evolutionary process that began billions of years ago in non-disease-causing microorganisms. This environmental resistome, its mobilization, and the conditions that facilitate its entry into human pathogens are at the heart of the current public health crisis in antibiotic resistance. Understanding the origins, evolution, and mechanisms of transfer of resistance elements is vital to our ability to adequately address this public health issue. Antimicrobial drug resistance is caused by microbial gene products that attenuate the activity of an antibiotic in an otherwise drug-sensitive organism. Mechanisms involved include modification of the drugs to less toxic derivatives or avoidance of their action by exclusion, target modification, and mutation of target-associated genes. The biologic effect of these resistance determinants is often highly dependent on genetic and organismal context; thus, resistance genes may be latent under certain conditions, only to be activated in others. Movement of these genes from 1 organism to another or an increase in their expression, for example, can trigger a resistance phenotype (1). Therefore, to understand its evolution and potential impact of resistance, a broad view of what constitutes resistance must be taken. Understanding is increasing that much of antimicrobial drug resistance originates in environmental bacteria that do not cause human disease (2,3). These organisms have evolved over millennia to sense, interact with, and metabolize small molecules and as a result have developed a plethora of mechanisms to modulate the activities of these compounds. The associated genes often offer some broader selective advantage and consequently have been mobilized and horizontally transferred to other microorganisms sharing their ecologic habitat. This dissemination increases the total effect of resistance determinants within the broad collection of environmental bacteria. Discharges of chemical agents (drugs, disinfectants, heavy metals, and other pollutants) into the environment can accelerate the lateral movement of resistance genes across bacterial populations by increasing selective pressure for maintenance of mobile genetic elements (MGEs) (4) or by increasing the rate of gene transfer (5). Furthermore, humans have created environments with unprecedented mixing opportunities between environmental bacteria and human pathogens in the presence of such selective agents through, for example, sewage and waste water treatment plants, chemical production factories, and the practice of spreading manure on farmland. These opportunities provide conditions that greatly facilitate gene mobilization. The result is a perfect storm of opportunity for bacterial human pathogens that exploits millions of years of evolution, uncounted microbial generations, and modern human activity. We outline some key aspects of our current understanding of the environmental antibiotic resistome, its mobilization, and the conditions that facilitate its spread through human activities and offer thoughts on existing knowledge gaps and research needs to mitigate their effects on human health.