all of biology. Confidence that bacterial diseases were completely under control was bolstered by a glut of new antibiotics on the market. Indeed, there was a pervasive perception among the medical community and the public as a whole that bacterial infectious diseases were no longer a problem since they could now be readily and effectively treated with antibiotics.
Unnoticed by all but a few researchers in the field and some pharmaceutical companies, the first cracks soon began to appear in the protective shield against bacterial diseases. This danger became more evident in the late 1970s. Antibiotics were no longer the highly profitable products they had once been, especially not compared to heart medications or tranquilizers, which needed to be taken daily for long periods of time. Additionally, new antibiotics were becoming harder to discover and more expensive to develop. One pharmaceutical company after another quietly cut back or dismantled its antibiotic discovery program. For a while, these cracks appeared not to matter, as there were enough new antibiotics that still worked on the bacteria that had become resistant to the old standbys like penicillin. Warnings from scientists that bacteria were becoming more resistant to antibiotics were largely ignored.
During the late 1980s, however, scientists and health officials began to notice an alarming increase in difficult-to-treat bacterial infections. By 1995, infectious diseases became one of the top five causes of death in the United States. Even with the AIDS epidemic in full swing, most infectious disease deaths were still caused by bacterial diseases, such as pneumonia and bacterial bloodstream infections (sepsis). Why was the incidence of bacterial pneumonia and sepsis increasing? For one, the population as a whole was aging, and older people are more susceptible to these diseases. For another, modern medicine had created a large and growing population of patients whose immune systems were temporarily disrupted due to cancer chemotherapy or immunosuppressive therapy following organ transplants, as well as due to other immune-compromising illnesses such as AIDS.
A development that caught many in the medical community by surprise was the appearance of new diseases that were dubbed emerging infectious diseases. In the past, scientists had assumed that any microorganism capable of causing disease would surely have done so by now, given the hundreds of thousands of years humans have occupied the planet. This view overlooked two important facts. First, bacteria can very rapidly change their genetic makeup to take advantage of new opportunities. Members of some bacterial populations are hypermutable, allowing them to try many genetic combinations to find the one most appropriate for the current environment experienced by that bacterium. Many bacteria can also acquire genes conferring new virulence traits or resistance to antibiotics from other related or even unrelated bacteria through a phenomenon known as horizontal gene transfer (HGT). Second, changing human practices, such as increased global travel, widespread use of air-conditioning, and the appearance of crowded intensive care wards in big hospitals, brought susceptible people into contact with microorganisms that had not previously had the opportunity to cause human infections.
A new category of disease-causing bacteria was recognized: opportunistic pathogens. These bacteria normally do not cause disease in healthy people, but can infect and cause disease in individuals whose defenses are compromised in some way. In fact, many of these pathogens are found normally in or on the human body and thus had been assumed to be innocuous. Others are bacteria commonly found in soil or aquatic environments. During the early antibiotic era, these soil bacteria were thought to be beneficial to humans because scientists were finding that many of them were producers of antibiotics. However, these bacteria were suddenly being seen as the only bacterium isolated from the blood, lungs, feces, or wounds of seriously ill patients. They also tend to exhibit a troubling, not-so-friendly characteristic. Because of the antibiotics present in their natural environment, they are often intrinsically resistant to a variety of antibiotics, which made infections by these opportunistic bacteria challenging to treat.
Scientists and physicians reluctantly began to realize that a decisive human victory over bacteria had not occurred. Not only were known pathogens changing to be more resistant to antibiotics or better able to cause disease, but also new pathogens with markedly different virulence traits were emerging. The infectious disease picture was changing in a way that made it increasingly difficult to predict new patterns of bacterial disease. The serious threat of antibiotic-resistant bacteria to human health both in the United States and the world was documented in 2013 by reports from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).
Bacteria, a Formidable Ancient Life Form
The brief foregoing account of how bacterial diseases have come into prominence as a major global health problem explored the recent past. However, to understand fully why no one should have been surprised by this development and why bacteria are such formidable opponents, it is necessary to take a closer look at the long history of bacteria, during which they were constantly forced to evolve and adapt to new conditions.
Today, we realize that Earth is a microbial planet. Bacteria were probably the first form of life to appear on Earth, about 3.5 to 4 billion years ago (Figure 1-1). Bacteria and another type of prokaryote, the archaea, ruled the world unchallenged for at least a billion years before the first eukaryotes appeared. During this period, they helped create the global geochemical cycles that made Earth habitable for larger life forms. Bacteria and archaea are master recyclers. Bacteria put the first molecular oxygen in Earth’s atmosphere, thereby creating the ozone layer, which protected Earth’s surface from the deadly radiation that had previously bombarded it, making life on Earth’s surface possible. By adding molecular oxygen to the atmosphere, bacteria created conditions that permitted the later evolution of oxygen-utilizing creatures, including humans.
Figure 1-1. Overview of microbial evolution. Microorganisms appeared 3.5 to 4 billion years ago and changed Earth such that eukaryotes could evolve.
In the course of their long history, bacteria developed a variety of metabolic capabilities that allowed them to survive under an impressive variety of conditions. There are bacteria that can obtain energy by oxidizing sulfides, reducing sulfate, oxidizing ammonia, reducing nitrate, and oxidizing methane—to name only a few of the vast number of metabolic types represented in the bacterial world. Bacteria also learned how to maximize the plasticity of their genomes, constantly acquiring new DNA and mutating or rearranging existing genes, thereby creating new capabilities that enabled them to colonize the many niches on Earth. So far, no part of Earth has been found to be free of bacteria and archaea. They are in arctic ice, the deep subsurface of landmasses, the surfaces and depths of the oceans, and boiling hot springs. The genetic plasticity that enabled evolution of such metabolically diverse organisms continues to serve bacteria today as they face new challenges and opportunities.
About a billion years after bacteria first appeared on Earth, the first eukaryotes, the single-celled protozoa, emerged. Disease-causing bacteria are often capable of doing so because they have developed strategies for evading phagocytosis (engulfment) or for surviving inside phagocytic cells. Evolution of such strategies could have begun soon after the appearance of the first protozoa, well in advance of the appearance of animals and humans. Some of the toxic proteins that disease-causing bacteria use to kill human cells might have originally evolved to allow bacteria to evade or survive feeding by their protozoal adversaries. Today, scientists are finding that some bacterial pathogens that are harmful to humans normally live inside amoebas in nature. If this view of bacterial evolution is correct, then there are likely to be more unidentified disease-causing bacteria in nature than we currently know.
As bacteria evolved diverse metabolic specialties, acquisition of bacteria or archaea as coinhabitants (endosymbionts) enabled eukaryotes to expand their metabolic diversity as well. Eukaryotes acquired bacterial endosymbionts (now known as mitochondria) that allowed them to gain energy through respiration and to regulate cellular metabolism, thereby also enabling them to become multicellular. Cells of what would
