Information

22.4C: Antibiotics: Are We Facing a Crisis? - Biology


LEARNING OBJECTIVES

  • Discuss antibiotic resistance.

The word antibiotic comes from the Greek word “anti” meaning “against” and “bios” meaning “life.” An antibiotic is a chemical, produced either by microbes or synthetically, that is hostile to the growth of other organisms. Today’s news and other media often address concerns about an antibiotic crisis. Are the antibiotics that easily treated bacterial infections in the past becoming obsolete? Are there new “superbugs”: bacteria that have evolved to become more resistant to our arsenal of antibiotics? Is this the beginning of the end of antibiotics? All these questions challenge the healthcare community.

One of the main causes of resistant bacteria is the abuse of antibiotics. The imprudent and excessive use of antibiotics has resulted in the natural selection of resistant forms of bacteria. The antibiotic kills most of the infecting bacteria; therefore, only the resistant forms remain. These resistant forms reproduce, resulting in an increase in the proportion of resistant forms over non-resistant ones. Another major misuse of antibiotics is in patients with colds or the flu, for which antibiotics are useless. There is also the excessive use of antibiotics in livestock along with the routine use of antibiotics in animal feed, both of which promote bacterial resistance. In the United States, 70 percent of the antibiotics produced are fed to animals. Because they are given to livestock in low doses, the probability of resistance developing is maximized. These resistant bacteria are readily transferred to humans.

One of the Superbugs: MRSA

The imprudent use of antibiotics has paved the way for bacteria to expand populations of resistant forms. For example, Staphylococcus aureus, often called “staph,” is a common bacterium that can live in the human body and is usually easily treated with antibiotics. A very dangerous strain, however, methicillin-resistant Staphylococcus aureus (MRSA) has made the news over the past few years. This strain is resistant to many commonly-used antibiotics, including methicillin, amoxicillin, penicillin, and oxacillin. MRSA can cause infections of the skin, but it can also infect the bloodstream, lungs, urinary tract, or sites of injury. While MRSA infections are common among people in healthcare facilities, they have also appeared in healthy people who have not been hospitalized, but who live or work in tight populations (like military personnel and prisoners). Researchers have expressed concern about the way this latter source of MRSA targets a much younger population than those residing in care facilities. The Journal of the American Medical Association (JAMA) reported that, among MRSA-afflicted persons in healthcare facilities, the average age is 68, whereas people with “community-associated MRSA” (CA-MRSA) have an average age of 23.

In summary, the medical community is facing an antibiotic crisis. Some scientists believe that after years of being protected from bacterial infections by antibiotics, we may be returning to a time in which a simple bacterial infection could again devastate the human population. Researchers are developing new antibiotics, but it takes many years of research and clinical trials, plus financial investments in the millions of dollars, to generate an effective and approved drug.

Key Points

  • In antibiotic resistance, antibiotics will kill most of the infecting bacteria leaving behind only the resistant forms, which reproduce, resulting in an increase in the proportion of resistant forms over non-resistant ones.
  • Cold and flu treatments and the medication of livestock are examples of antibiotic misuse responsible for bacterial resistance.
  • Methicillin-resistant Staphylococcus aureus (MRSA) is an example of a dangerous antibiotic-resistant strain of bacteria that can infect sick, as well as healthy people.
  • Due to the growing resistance to antibiotics, scientists believe that we may be returning to a time in which a simple bacterial infection could again detrimentally impact human populations.

Key Terms

  • antibiotic: any substance that can destroy or inhibit the growth of bacteria and similar microorganisms

Reference

Naimi, TS, LeDell, KH, Como-Sabetti, K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 290 (2003): 2976–84, doi: 10.1001/jama.290.22.2976.


73 Bacterial Diseases in Humans

By the end of this section, you will be able to do the following:

  • Identify bacterial diseases that caused historically important plagues and epidemics
  • Describe the link between biofilms and foodborne diseases
  • Explain how overuse of antibiotics may be creating “super bugs”
  • Explain the importance of MRSA with respect to the problems of antibiotic resistance

To a prokaryote, humans may be just another housing opportunity. Unfortunately, the tenancy of some species can have harmful effects and cause disease. Bacteria or other infectious agents that cause harm to their human hosts are called pathogens . Devastating pathogen-borne diseases and plagues, both viral and bacterial in nature, have affected humans and their ancestors for millions of years. The true cause of these diseases was not understood until modern scientific thought developed, and many people thought that diseases were a “spiritual punishment.” Only within the past several centuries have people understood that staying away from afflicted persons, disposing of the corpses and personal belongings of victims of illness, and sanitation practices reduced their own chances of getting sick.

Epidemiologists study how diseases are transmitted and how they affect a population. Often, they must following the course of an epidemic —a disease that occurs in an unusually high number of individuals in a population at the same time. In contrast, a pandemic is a widespread, and usually worldwide, epidemic. An endemic disease is a disease that is always present, usually at low incidence, in a population.


The Issue:

Antimicrobial Resistance (AMR) occurs when microorganisms change with exposure to antimicrobial drugs (such as antibiotics, antifungals and antivirals). Microorganisms that develop AMR are sometimes referred to as “superbugs”.

  • In 2014, the WHO reported that AMR “is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country…[AMR] is a major threat to public health.”

According to the CDC, the annual U.S. impact from drug-resistant infections includes over 2.8 million illnesses – over 35,000 of which result in death.

  • Drug resistant infections cost the US $20-25 billion in excess direct health expenditures, with another $35 billion in additional costs to society for lost productivity.

The crisis is being exacerbated by the fact that US scientific research and development (R&D) has largely shifted away from investment in new antimicrobials to combat these infections due to the unique scientific, regulatory and economic challenges of antimicrobial R&D.

  • Less than 5% of pharmaceutical investment goes towards antimicrobial development.
  • Only 2 of the top 50 top drug companies in the world is still developing antimicrobials.
  • Over 95% of the products in development are being developed by smaller companies – like those that comprise the AWG.

Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research for the FDA testified in a hearing before the House E&C Committee, Subcommittee on Health in September 2014: “The decline in antibacterial drug research and development (R&D) in the private sector, at a time when serious antibiotic resistant infections are on the rise, is a tremendous public health problem, resulting in a very serious unmet medical need.”


The ERA of antibiotic discovery

The glorious years of antibiotic discovery, development and production took place in the period between 1940 and the 1960s. Discovery in later years continued but not as rapidly as in the early years. The most important antibiotics include the penicillins, cephalosporins, tetracyclines, aminoglycosides, chloramphenicol, macrolides and glycopeptides. Antibiotics have been crucial in the increase in life expectancy in the United States from 47 years in 1900 to 74 years for males and to 80 years for females in the year 2000. 4

Over 10 000 microbial secondary metabolites have been discovered. 5 The filamentous bacteria, that is, the actinomycetes, are amazingly prolific in the number of antibiotics which they can produce. About 75% of known antibiotics are produced by actinomycetes and about 75% of these are made by a single genus, that is, Streptomyces. Of antibiotics used in medicine, more than 90% originate from the actinomycetes. In a typical actinomycete, 23–30 gene clusters (about 5% of the genome) are devoted to secondary metabolism. 6 Also, important are non-filamentous bacteria, such as species of Bacillus, which can produce over 60 antibiotics. Indeed, 12% of known antibiotics are produced by non-filamentous bacteria. In addition, some useful antibiotics, such as fusidic acid, are made by fungi (Fusidium coccineum). 7


Could liposomes be the answer to our antibiotic crisis?

It’s no secret we are facing an antibiotic crisis. Overuse has caused widespread antibiotic resistance, leading the World Health Organisation to declare we are "headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill." Scientists from the University of Bern have developed a new non-antibiotic compound that treats severe bacterial infections and avoids the problem of bacterial resistance.

We have a lot to thank antibiotics for. Before the discovery of penicillin 90 years ago pneumonia, tuberculosis, or even an infected cut could be fatal. And today, many of our routine surgical procedures are dependent on the ability to fight infections with antibiotics.

However, up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary or inappropriate according to the Centers for Disease Control, and this overuse is the single most important factor leading to antibiotic resistance.

Although there have been many developments over the years, such as antibiotic "smart bombs", the difficulty has been eliminating bacteria without also promoting bacterial resistance. This has created a need to strive for non-antibiotic approaches, including "ninja polymers" and more natural treatments like raw honey and natural proteins.

This latest non-antibiotic compound developed by Eduard Babiychuk and Annette Draeger from the Institute of Anatomy, University of Bern, and tested by a team of international scientists, was created by engineering artificial nanoparticles made of lipids, "liposomes" that closely resemble the membrane of host cells.

In clinical medicine, liposomes are used to deliver specific medication into the body of patients. The scientists in Bern have created liposomes that act as bait, attracting bacterial toxins so they can be isolated and neutralized, thereby protecting host cells from a dangerous toxin attack. Without toxins, the bacteria are rendered defenseless and can be eliminated by the host's own immune system. Mice which were treated with the liposomes after experimental, fatal septicemia survived without additional antibiotic therapy.

"We have made an irresistible bait for bacterial toxins. The toxins are fatally attracted to the liposomes, and once they are attached, they can be eliminated easily without danger for the host cells," says Eduard Babiychuk who directed the study.

"Since the bacteria are not targeted directly, the liposomes do not promote the development of bacterial resistance", adds Annette Draeger.


What is being done to combat antibiotic resistance?

The most obvious way to combat antibiotic resistance is to minimize how much we use antibiotics. Doctors and clinicians have become more wary of prescribing antibiotics for infections that could potentially resolve themselves, and programs like “Get Smart”, run by the CDC, aim to increase awareness in patients about when and how antibiotics should be administered [10].

The overuse of antibiotics in the meat industry has also garnered much attention and the FDA has now recommends that antibiotic use be reserved for sick animals only. As of now these measures are on a voluntary basis, but many believe that stricter regulations must be enacted to truly compel change [11].

Figure 4:Solutions to Antibiotic Resistance

Both academic labs and biotech companies are exploring better diagnostic tools for detecting antibiotic resistant bacteria [12]. Generally, resistant infections are detected through trial and error doctors will administer one antibiotic and then switch to another if the bacteria do not respond. Not only does this approach waste time, it can also have unexpected negative effects [13]. More efficient methods of determining bacterial sensitivity to antibiotics could greatly enhance treatment for infections, and help contain potential outbreaks.

Researchers are also investigating new strategies to kill multi-drug resistant bacteria. One approach is to try and find new antibiotics that target different processes in bacteria. Last year researchers at Northeastern reported the discovery of a new antibiotic, Teixobactin, which is effective against Mycobacterium tuberculosis and MRSA. This drug works differently than any antibiotic currently in use, and while research on Teixobactin is still in its infant stages, bacteria resistant to this antibiotic have yet to be discovered [14].

Similarly some researchers are interested in targeting the strategy of resistance itself. Augmentin, a mix of amoxicillin and a second molecule that blocks the bacterial resistance mechanism to amoxicillin, is a successful example of this strategy. Efflux pumps that remove antibiotics, the broadest and most utilized resistance mechanism, are also intriguing targets for these types of combination therapies [4].

Since the release of the WHO survey, and in the wake of multiple news stories about “superbugs,” US funding sources have announced a plan to increase federal spending on antibiotic research by more than 50%. This money could help prevent outbreaks by supporting improved infrastructure and hygiene practices in clinics and hospitals. Additionally, these grants will fund academic research on antibiotic resistance through allocation of grants by the National Institute of Health [15]. This burst in funding could have a major impact on research into the previously described approaches to combat antibiotic resistance.

While the pursuit of novel treatments and diagnostics for antibiotic resistant infections will remain essential research focuses in biotech and academia, adjusting human behavior and attitudes towards antibiotics is likely the most significant hurdle we face. The survey mentioned at the beginning of this article made it abundantly clear that there is a serious lack of communication among clinicians, researchers, and the general public. Since the results of this survey were released, the WHO has launched a global campaign to improve education on the dangers and causes of antibiotic resistance [3]. It is likely that, in the next several years, more campaigns and educational programs like this will follow.

Of course, antibiotic resistance is not a problem with a simple solution – as long as antibiotics are still in the environment, bacteria will find a way to evade their toxic effects. However, raising awareness about how humans have contributed to this world health crisis, and examining what we can do to slow its progression, will be our best chance at defeating, or at least slowing down, these “superbugs.”

Alexandra Cantley is a 5 th year graduate student in the Chemical Biology Program at Harvard University. Her research in the Clardy Lab focuses on the exploration of chemical interactions between bacteria and other microorganisms.


Biology 171

By the end of this section, you will be able to do the following:

  • Identify bacterial diseases that caused historically important plagues and epidemics
  • Describe the link between biofilms and foodborne diseases
  • Explain how overuse of antibiotics may be creating “super bugs”
  • Explain the importance of MRSA with respect to the problems of antibiotic resistance

To a prokaryote, humans may be just another housing opportunity. Unfortunately, the tenancy of some species can have harmful effects and cause disease. Bacteria or other infectious agents that cause harm to their human hosts are called pathogens . Devastating pathogen-borne diseases and plagues, both viral and bacterial in nature, have affected humans and their ancestors for millions of years. The true cause of these diseases was not understood until modern scientific thought developed, and many people thought that diseases were a “spiritual punishment.” Only within the past several centuries have people understood that staying away from afflicted persons, disposing of the corpses and personal belongings of victims of illness, and sanitation practices reduced their own chances of getting sick.

Epidemiologists study how diseases are transmitted and how they affect a population. Often, they must following the course of an epidemic —a disease that occurs in an unusually high number of individuals in a population at the same time. In contrast, a pandemic is a widespread, and usually worldwide, epidemic. An endemic disease is a disease that is always present, usually at low incidence, in a population.

Long History of Bacterial Disease

There are records about infectious diseases as far back as 3000 B.C. A number of significant pandemics caused by bacteria have been documented over several hundred years. Some of the most memorable pandemics led to the decline of cities and entire nations.

In the 21 st century, infectious diseases remain among the leading causes of death worldwide, despite advances made in medical research and treatments in recent decades. A disease spreads when the pathogen that causes it is passed from one person to another. For a pathogen to cause disease, it must be able to reproduce in the host’s body and damage the host in some way.

The Plague of Athens

In 430 B.C., the Plague of Athens killed one-quarter of the Athenian troops who were fighting in the great Peloponnesian War and weakened Athens’s dominance and power. The plague impacted people living in overcrowded Athens as well as troops aboard ships that had to return to Athens. The source of the plague may have been identified recently when researchers from the University of Athens were able to use DNA from teeth recovered from a mass grave. The scientists identified nucleotide sequences from a pathogenic bacterium, Salmonella enterica serovar Typhi ((Figure)), which causes typhoid fever. 1 This disease is commonly seen in overcrowded areas and has caused epidemics throughout recorded history.


Bubonic Plagues

From 541 to 750, the Plague of Justinian, an outbreak of what was likely bubonic plague, eliminated one-quarter to one-half of the human population in the eastern Mediterranean region. The population in Europe dropped by 50 percent during this outbreak. Astoundingly, bubonic plague would strike Europe more than once!

Bubonic plague is caused by the bacterium Yersinia pestis. One of the most devastating pandemics attributed to bubonic plague was the Black Death (1346 to 1361). It is thought to have originated in China and spread along the Silk Road, a network of land and sea trade routes, to the Mediterranean region and Europe, carried by fleas living on black rats that were always present on ships. The Black Death was probably named for the tissue necrosis ((Figure)c) that can be one of the symptoms. The “buboes” of bubonic plague were painfully swollen areas of lymphatic tissue. A pneumonic form of the plague, spread by the coughing and sneezing of infected individuals, spreads directly from human to human and can cause death within a week. The pneumonic form was responsible for the rapid spread of the Black Death in Europe. The Black Death reduced the world’s population from an estimated 450 million to about 350 to 375 million. Bubonic plague struck London yet again in the mid-1600s ((Figure)). In modern times, approximately 1,000 to 3,000 cases of plague arise globally each year, and a “sylvatic” form of plague, carried by fleas living on rodents such as prairie dogs and black footed ferrets, infects 10 to 20 people annually in the American Southwest. Although contracting bubonic plague before antibiotics meant almost certain death, the bacterium responds to several types of modern antibiotics, and mortality rates from plague are now very low.


Watch a video on the modern understanding of the Black Death—bubonic plague in Europe during the 14 th century.

Migration of Diseases to New Populations

One of the negative consequences of human exploration was the accidental “biological warfare” that resulted from the transport of a pathogen into a population that had not previously been exposed to it. Over the centuries, Europeans tended to develop genetic immunity to endemic infectious diseases, but when European conquerors reached the western hemisphere, they brought with them disease-causing bacteria and viruses, which triggered epidemics that completely devastated many diverse populations of Native Americans, who had no natural resistance to many European diseases. It has been estimated that up to 90 percent of Native Americans died from infectious diseases after the arrival of Europeans, making conquest of the New World a foregone conclusion.

Emerging and Re-emerging Diseases

The distribution of a particular disease is dynamic. Changes in the environment, the pathogen, or the host population can dramatically impact the spread of a disease. According to the World Health Organization (WHO), an emerging disease ((Figure)) is one that has appeared in a population for the first time, or that may have existed previously but is rapidly increasing in incidence or geographic range. This definition also includes re-emerging diseases that were previously under control. Approximately 75 percent of recently emerging infectious diseases affecting humans are zoonotic diseases. Zoonoses are diseases that primarily infect animals but can be transmitted to humans some are of viral origin and some are of bacterial origin. Brucellosis is an example of a prokaryotic zoonosis that is re-emerging in some regions, and necrotizing fasciitis (commonly known as flesh-eating bacteria) has been increasing in virulence for the last 80 years for unknown reasons.


Some of the present emerging diseases are not actually new, but are diseases that were catastrophic in the past ((Figure)). They devastated populations and became dormant for a while, just to come back, sometimes more virulent than before, as was the case with bubonic plague. Other diseases, like tuberculosis, were never eradicated but were under control in some regions of the world until coming back, mostly in urban centers with high concentrations of immunocompromised people. WHO has identified certain diseases whose worldwide re-emergence should be monitored. Among these are three viral diseases (dengue fever, yellow fever, and zika), and three bacterial diseases (diphtheria, cholera, and bubonic plague). The war against infectious diseases has no foreseeable end.


Foodborne Diseases

Prokaryotes are everywhere: They readily colonize the surface of any type of material, and food is not an exception. Most of the time, prokaryotes colonize food and food-processing equipment in the form of a biofilm, as we have discussed earlier. Outbreaks of bacterial infection related to food consumption are common. A foodborne disease (commonly called “food poisoning”) is an illness resulting from the consumption the pathogenic bacteria, viruses, or other parasites that contaminate food. Although the United States has one of the safest food supplies in the world, the U.S. Centers for Disease Control and Prevention (CDC) has reported that “76 million people get sick, more than 300,000 are hospitalized, and 5,000 Americans die each year from foodborne illness.”

The characteristics of foodborne illnesses have changed over time. In the past, it was relatively common to hear about sporadic cases of botulism, the potentially fatal disease produced by a toxin from the anaerobic bacterium Clostridium botulinum. Some of the most common sources for this bacterium were non-acidic canned foods, homemade pickles, and processed meat and sausages. The can, jar, or package created a suitable anaerobic environment where Clostridium could grow. Proper sterilization and canning procedures have reduced the incidence of this disease.

While people may tend to think of foodborne illnesses as associated with animal-based foods, most cases are now linked to produce. There have been serious, produce-related outbreaks associated with raw spinach in the United States and with vegetable sprouts in Germany, and these types of outbreaks have become more common. The raw spinach outbreak in 2006 was produced by the bacterium E. coli serotype O157:H7. A serotype is a strain of bacteria that carries a set of similar antigens on its cell surface, and there are often many different serotypes of a bacterial species. Most E. coli are not particularly dangerous to humans, but serotype O157:H7 can cause bloody diarrhea and is potentially fatal.

All types of food can potentially be contaminated with bacteria. Recent outbreaks of Salmonella reported by the CDC occurred in foods as diverse as peanut butter, alfalfa sprouts, and eggs. A deadly outbreak in Germany in 2010 was caused by E. coli contamination of vegetable sprouts ((Figure)). The strain that caused the outbreak was found to be a new serotype not previously involved in other outbreaks, which indicates that E. coli is continuously evolving. Outbreaks of listeriosis, due to contamination of meats, raw cheeses, and frozen or fresh vegetables with Listeria monocytogenes, are becoming more frequent.


Biofilms and Disease

Recall that biofilms are microbial communities that are very difficult to destroy. They are responsible for diseases such as Legionnaires’ disease, otitis media (ear infections), and various infections in patients with cystic fibrosis. They produce dental plaque and colonize catheters, prostheses, transcutaneous and orthopedic devices, contact lenses, and internal devices such as pacemakers. They also form in open wounds and burned tissue. In healthcare environments, biofilms grow on hemodialysis machines, mechanical ventilators, shunts, and other medical equipment. In fact, 65 percent of all infections acquired in the hospital (nosocomial infections) are attributed to biofilms. Biofilms are also related to diseases contracted from food because they colonize the surfaces of vegetable leaves and meat, as well as food-processing equipment that isn’t adequately cleaned.

Biofilm infections develop gradually and may not cause immediate symptoms. They are rarely resolved by host defense mechanisms. Once an infection by a biofilm is established, it is very difficult to eradicate, because biofilms tend to be resistant to most methods used to control microbial growth, including antibiotics. The matrix that attaches the cells to a substrate and to other another protects the cells from antibiotics or drugs. In addition, since biofilms grow slowly, they are less responsive to agents that interfere with cell growth. It has been reported that biofilms can resist up to 1,000 times the antibiotic concentrations used to kill the same bacteria when they are free-living or planktonic. An antibiotic dose that large would harm the patient therefore, scientists are working on new ways to get rid of biofilms.

Antibiotics: Are We Facing a Crisis?

The word antibiotic comes from the Greek anti meaning “against” and bios meaning “life.” An antibiotic is a chemical, produced either by microbes or synthetically, that is hostile to or prevents the growth of other organisms. Today’s media often address concerns about an antibiotic crisis. Are the antibiotics that easily treated bacterial infections in the past becoming obsolete? Are there new “superbugs”—bacteria that have evolved to become more resistant to our arsenal of antibiotics? Is this the beginning of the end of antibiotics? All these questions challenge the healthcare community.

One of the main causes of antibiotic resistance in bacteria is overexposure to antibiotics. The imprudent and excessive use of antibiotics has resulted in the natural selection of resistant forms of bacteria. The antibiotic kills most of the infecting bacteria, and therefore only the resistant forms remain. These resistant forms reproduce, resulting in an increase in the proportion of resistant forms over non-resistant ones. In addition to transmission of resistance genes to progeny, lateral transfer of resistance genes on plasmids can rapidly spread these genes through a bacterial population. A major misuse of antibiotics is in patients with viral infections like colds or the flu, against which antibiotics are useless. Another problem is the excessive use of antibiotics in livestock. The routine use of antibiotics in animal feed promotes bacterial resistance as well. In the United States, 70 percent of the antibiotics produced are fed to animals. These antibiotics are given to livestock in low doses, which maximize the probability of resistance developing, and these resistant bacteria are readily transferred to humans.

Watch a recent news report on the problem of routine antibiotic administration to livestock and antibiotic-resistant bacteria.

One of the Superbugs: MRSA

The imprudent use of antibiotics has paved the way for the expansion of resistant bacterial populations. For example, Staphylococcus aureus, often called “staph,” is a common bacterium that can live in the human body and is usually easily treated with antibiotics. However, a very dangerous strain, methicillin-resistant Staphylococcus aureus (MRSA) has made the news over the past few years ((Figure)). This strain is resistant to many commonly used antibiotics, including methicillin, amoxicillin, penicillin, and oxacillin. MRSA can cause infections of the skin, but it can also infect the bloodstream, lungs, urinary tract, or sites of injury. While MRSA infections are common among people in healthcare facilities, they have also appeared in healthy people who haven’t been hospitalized, but who live or work in tight populations (like military personnel and prisoners). Researchers have expressed concern about the way this latter source of MRSA targets a much younger population than those residing in care facilities. The Journal of the American Medical Association reported that, among MRSA-afflicted persons in healthcare facilities, the average age is 68, whereas people with “community-associated MRSA” ( CA-MRSA ) have an average age of 23. 2


In summary, the medical community is facing an antibiotic crisis. Some scientists believe that after years of being protected from bacterial infections by antibiotics, we may be returning to a time in which a simple bacterial infection could again devastate the human population. Researchers are developing new antibiotics, but it takes many years of research and clinical trials, plus financial investments in the millions of dollars, to generate an effective and approved drug.

Epidemiologist Epidemiology is the study of the occurrence, distribution, and determinants of health and disease in a population. It is, therefore, part of public health. An epidemiologist studies the frequency and distribution of diseases within human populations and environments.

Epidemiologists collect data about a particular disease and track its spread to identify the original mode of transmission. They sometimes work in close collaboration with historians to try to understand the way a disease evolved geographically and over time, tracking the natural history of pathogens. They gather information from clinical records, patient interviews, surveillance, and any other available means. That information is used to develop strategies, such as vaccinations ((Figure)), and design public health policies to reduce the incidence of a disease or to prevent its spread. Epidemiologists also conduct rapid investigations in case of an outbreak to recommend immediate measures to control it.

An epidemiologist has a bachelor’s degree, plus a master’s degree in public health (MPH). Many epidemiologists are also physicians (and have an M.D. or D.O degree), or they have a Ph.D. in an associated field, such as biology or microbiology.


Section Summary

Some prokaryotes are human pathogens. Devastating diseases and plagues have been among us since early times and remain among the leading causes of death worldwide. Emerging diseases are those rapidly increasing in incidence or geographic range. They can be new or re-emerging diseases (previously under control). Many emerging diseases affecting humans originate in animals (zoonoses), such as brucellosis. A group of re-emerging bacterial diseases recently identified by WHO for monitoring include bubonic plague, diphtheria, and cholera. Foodborne diseases result from the consumption of food contaminated with food, pathogenic bacteria, viruses, or parasites.

Some bacterial infections have been associated with biofilms: Legionnaires’ disease, otitis media, and infection of patients with cystic fibrosis. Biofilms can grow on human tissues, like dental plaque colonize medical devices and cause infection or produce foodborne disease by growing on the surfaces of food and food-processing equipment. Biofilms are resistant to most of the methods used to control microbial growth. The excessive use of antibiotics has resulted in a major global problem, since resistant forms of bacteria have been selected over time. A very dangerous strain, methicillin-resistant Staphylococcus aureus (MRSA), has wreaked havoc recently across the world.

Free Response

Explain the reason why the imprudent and excessive use of antibiotics has resulted in a major global problem.

Antibiotics kill bacteria that are sensitive to them thus, only the resistant ones will survive. These resistant bacteria will reproduce, and therefore, after a while, there will be only resistant bacteria.

Researchers have discovered that washing spinach with water several times does not prevent foodborne diseases due to E. coli. How can you explain this fact?

E. coli colonizes the surface of the leaf, forming a biofilm that is more difficult to remove than free (planktonic) cells. Additionally, bacteria can be taken up in the water that plants are grown in, thereby entering the plant tissues rather than simply residing on the leaf surface.

Footnotes

    Papagrigorakis MJ, Synodinos PN, and Yapijakis C. Ancient typhoid epidemic reveals possible ancestral strain of Salmonella enterica serovar Typhi. Infect Genet Evol 7 (2007): 126–7, Epub 2006 Jun. Naimi, TS, LeDell, KH, Como-Sabetti, K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 290 (2003): 2976–84, doi: 10.1001/jama.290.22.2976.

Glossary


Antibiotic Resistance: Facing the Challenges of Bacterial Infections

In 1928 Alexander Fleming made his groundbreaking discovery of penicillin. Antibiotics have since been our most powerful weapons against bacterial infections: The average life expectancy significantly increased and previously risky surgeries became standard medical interventions that revolutionized medicine. Nowadays resistance development casts its shadow on the once shiny drugs that saved millions of lives. Today more than 90% of pathogenic Staphylococcus aureus are resistant against penicillin. The full depth of the problem has long been obscured by the seemingly unlimited number of antibiotics. However, in the last years the number of new antibiotics has drastically decreased while the development and spread of resistances has dramatically increased.

The Resistance Problem
Bacterial resistance is a multifaceted problem with a broad range of reasons for their development, evolution, and distribution:

1) Only a relatively small number of molecular targets in bacterial cells is attacked by the majority of antibiotics [1]. For instance, β-lactams inhibit enzymes of the cell wall biosynthesis, aminoglycosides interrupt bacterial protein biosynthesis by inhibiting the 30S ribosomal subunit, and quinolones inhibit cell division by targeting the DNA gyrase complex (fig. 1).

2) While the number of antibacterial molecules seems to be enormous, the actual number of antibiotic classes is very small (fig. 1). The class of β-lactams for instance comprises various groups that taken together are dominating the market with approximately 65% of all antibiotics [2]. Antibiotics of one class frequently have the same molecular targets and thus resistance development against one antibiotic easily confers resistance to additional antibiotics.

3) Some resistance mechanisms apply for multiple antibiotics of various classes. Resistance development usually involves enzymatic inactivation of the antibiotic, alterations of the target enzyme, by-pass mechanisms, efflux pumps, and permeability barriers [3]. A single drug efflux system for instance can pump out a variety of different antibiotic classes [4].

4) Resistance genes can be easily spread by horizontal gene transfer. Bacterial resistance against antibiotics does not have to evolve de novo for every antibiotic in a strain or species. Horizontal gene transfer by conjugation, transformation, and transduction easily disseminates antibiotic resistances from one species to another [5].

5) Antibiotics have been over- and misused extensively for the treatment of simple self-resolving infections, prophylaxis, and household products. However, the by far most extensive use of antibiotics has been in livestock. In the US 80% of antibiotics are not for the treatment of human diseases but used in farm animals [6]. Thus, antibiotics are released in large quantities into the environment resulting in increasing resistance development.

6) Our bodies host 10-times as many bacterial cells as human cells. Many of these bacteria are facultative pathogens that may lead to severe infections when they accidentally get in the wrong place. Antibiotic treatment can result in the colonization by resistant facultative pathogens like MRSA strains and clearance of beneficial bacteria whose niches can be taken over by resistant strains [7].

The Antibiotic Crisis
Rapid evolution of antibiotic resistance continues to threaten the treatment of bacterial infections and requires the development of new antibiotics and alternative strategies. However, the development of new antibiotics has decreased over the last decades. In the years 2004 to 2014 a total of only eight new antibiotics were released to the market while in the years 1980 to 1990 it had been 46 new antibiotics and combination drugs. Among the antibiotics approved in the 80's were blockbusters like ciprofloxacin and azithromycin as well as several of the drugs that are still today on the WHO list of essential medicines.

Multiple reasons contribute to why antibiotic development has been abandoned by many big players in the pharmaceutical industry. Resistance development has shortened the life span of antibiotics while development to market approval is a long and expensive process that often takes a decade or more. Developmental risks are high and 90% of drugs fail during the long path from preclinical studies to market approval [8]. Finally, developmental costs and risks have to be compensated by market returns which again are threatened by emergence of resistances and patent expiry.

Also, it has become hard to find entirely new classes of antibiotics and the antibiotics approved in the past ten years are mostly based on known structures.

We are thus facing the problem of a steadily decreasing number of new antibiotics while resistance development is speeding up and multi-drug resistant strains are spreading rapidly. If this development continues, high mortalities for simple bacterial infections and high risks for normal surgeries will mark the upcoming post-antibiotic era.

Strategies for the Future
What can we do about this imminent threat and how can Chemistry and Biology contribute to alternative solutions? First of all I do not think that we will be able to completely replace antibiotics any time in the near future. Antibiotics are too important as last resort for the treatment of highly progressed and life threatening bacterial infections like sepsis, where rapid clearance of the infective agent is required to prevent death of the patient. We thus need to take action to save these valuable drugs:

The use of antibiotics should be limited to the treatment of actual infections and banned from use in household products and as growth enhancers for livestock. Over-the-counter sales in pharmacies should be restricted worldwide and limited to controlled applications in hospitals. Hospitals in turn have to take more responsibility for the resistance problematic, i.e. limiting application of antibiotics to the absolute necessary and establishing strict policies using the model of the Dutch MRSA search-and-destroy policy [9].

Advanced diagnostic techniques have become available that allow the rapid identification of pathogens and resistance markers before treatment so that customized narrow spectrum drugs can be applied. While broad spectrum antibiotics easily lead to resistance development of commensal bacteria and colonization with resistant strains, narrow spectrum drugs could prevent the disruption of the beneficial human microbiome. Combination therapies with different antibiotics and combinations of antibiotics with drugs that target resistance like β-lactamase inhibitors have been already applied for years and may become the predominant antibiotic strategy in the future to combat resistant pathogens.

For the majority of infectious diseases, however, antibiotics would actually not be necessary if alternatives were available. Such alternatives could be anti-virulence strategies that do not kill but disarm bacteria. The concept is simple: small molecules inhibit enzymes that are essential for infection rendering the bacterium disarmed [10]. Such infection related functions can be virulence factors like toxins and extracellular enzymes, proteins for adhesion to eukaryotic cells, type III secretion systems, or central regulators of virulence. Anti-virulence strategies also include inhibiting population behavior like biofilm formation or bacterial coordination by quorum sensing. Once the bacteria are disarmed the host immune response eventually will clear the intruders. It is proposed that some anti-virulence strategies would be less prone to resistance development, as they don't exert direct selective pressure. Anti-virulence strategies are in development and have already proven successful in animal models [11]. Applications could be preventive care after surgeries, treatment of chronic and recurrent infections, as well as most other not immediately life-threatening diseases.

Strategies of the future also may involve lytic bacteriophages as narrow spectrum agents against certain pathogens [12]. Phage therapy may have several advantages over antibiotics like the reproduction of the therapeutic agent in the host body and accumulation at the site of infection [13]. Further strategies may involve vaccinations against key pathogens which, however, can only be used for prophylaxis and not for treatment of an ongoing infection [14]. Vaccines against multi-drug resistant Staphylococcus aureus (MRSA) are currently under development. In contrast to vaccines, antibodies can be even used therapeutically as narrow spectrum drugs [15].

Further preventive methods may include material modifications such as impregnating catheters and implants with anti-biofilm agents or antibacterial nanoparticles [16]. Emerging physical treatment technologies like non-thermal gas plasmas -ionized gas generated by electric discharge - are currently in clinical trial and could be used for efficient treatment of wound infections [17]. Finally, supporting and controlling our beneficial microbial flora could be a major strategy for the prevention of infections in the future. Commensal bacteria are the first line of defense that physically occupy the existing niches of the human body, compete with intruding microbes, and produce a diversity of anti-bacterial and anti-fungal compounds and thereby prevent the invasion of pathogenic strains. Understanding the complex interactions in the microbiome and its importance for human health may help us in the future to preserve and directly control the composition of beneficial bacteria in our microbiome that strengthen our immune system and protect us from bacterial infections.

Conclusions
Antibiotic resistance poses a serious threat to our society and has led to an unfolding crisis for healthcare. Immediate actions should be taken to reduce the development and spreading of resistance to save antibiotics for the treatment of life-threatening infections. Alternatives to antibiotics are urgently needed and instead of a single strategy we will have to develop a broad mixture and combinations of narrow spectrum drugs and therapies that along with faster and more specific diagnostic methods can be applied to effectively treat infections. These strategies should simultaneously preserve the beneficial bacteria of the human microbiome and reduce the risk of resistance development and colonization with resistant strains.

Acknowledgement
My research is supported by the Emmy Noether program of DFG, the Zukunftskolleg of the University of Konstanz, and the Fonds der Chemischen Industrie. I also thank my mentor Andreas Marx for his support.

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Abstract

Synthetic biology offers a new path for the exploitation and improvement of natural products to address the growing crisis in antibiotic resistance. All antibiotics in clinical use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector. Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs. Harnessing synthetic biology thinking and strategies can provide new molecules and expand chemical diversity of known antibiotic scaffolds to provide much needed new drug leads. The glycopeptide antibiotics offer paradigmatic scaffolds suitable for such an approach. We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biology can expand antibiotic chemical diversity to help address the growing resistance crisis.


22.4C: Antibiotics: Are We Facing a Crisis? - Biology

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