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Overview of the Problem

History of Antibiotics and AR

Antibiotics are chemical substances, usually produced by living microorganisms, which kill or inhibit the growth of other microorganisms.1 Many antibiotics are naturally produced by bacteria or fungi. In natural environments, these compounds are produced at subinhibitory concentrations to facilitate interaction and communication with, and protection against, other microbes. Antibiotic resistance (AR), the ability of microorganisms to remain viable and multiply in the presence of antibiotics, is a natural phenomenon, driven by the ability of microorganisms to adapt to environmental pressures through genetic mutations and sharing of genetic material.2 Adaptation to the selective pressure of antibiotics can occur in vivo as well as in built and natural environments.2 Bacteria have developed AR characteristics throughout history, and genes conferring resistance to antibiotics that are used clinically today have been identified in DNA obtained from 30,000-year-old Beringian permafrost sediments and cave environments.3,4 Antibiotics are a type of antimicrobial, which is a broader group of agents used to treat infections caused by microorganisms (e.g., bacteria, viruses, fungi). Although antimicrobial resistance of other types can present clinical and public health challenges, this chapter will focus on antibiotics.

Human discovery of antibiotics revolutionized medicine, providing a cure for many previously fatal and debilitating infectious diseases. It was not long after the discovery of antibiotics that the medical community became aware that the use of antibiotics was associated with consequences. Sir Alexander Fleming received the Nobel Prize in 1945 for his discovery of penicillin. That same year, Fleming warned of the risk of bacteria becoming resistant to penicillin and cautioned the medical community to be thoughtful in its use.5,6 In modern times, a widespread AR crisis that significantly impacts our ability to treat infections is driven by the massive and at times inappropriate use of antibiotics. Because AR can be directly and indirectly influenced by antibiotic exposure, the problem of AR parallels the use patterns of clinically important drugs. Clinical resistance can appear within a few years of a drug’s introduction.7,8 The nature of this adaptation means that we need to continuously develop new antibiotics. At the current pace of spread, the global problem of AR is estimated to result in millions of deaths and US$100 trillion of expense by 2050.9 This crisis highlights the need for judicious use of antibiotics, development of new antibiotics, and alternative approaches to killing or slowing the growth of bacteria.

Genetics of AR

Acquired Resistance

Bacteria acquire resistance through two mechanisms: point mutation and horizontal gene transfer (HGT) as described below.

Spontaneous Mutation

Point mutation, or changes to individual DNA base pairs, contributes to bacterial genetic variability and drives bacterial adaptation to external stressors like antibiotics. Clonal replication of organisms ...

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