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Part 1

Phage Philes: Part 1

Introduction to Bacteriophage

Bacteriophages: What are they?

Bacteriophage means “bacteria eater.” Referred to simply as phages, these microbes are viruses that infect and kill bacteria. As the most common biological entity in nature, phages have been responsible for constraining bacterial growth since microbial life emerged some 3.5 billion years ago. Remarkably, phages kill up to 40% of all marine bacteria every 24 hours.(1)

Bacteriophages may be the most abundant thing you have never heard of. Estimates suggest something like 4.8 x 10(31) phages sprinkled across the world.(1) That is 4.8 nonillion or 48,000,000,000,000,000,000,000,000,000,000 bacteria-killing machines. This inconceivably large number is the equivalent of about one trillion phages for every grain of sand on Earth.

Several thousands of phage varieties exist, each specialized to infect only one or a few types of bacteria. Like other viruses, phages cannot replicate independently and must hijack bacteria’s cellular machinery. To do this, they attach to the outside of a bacterium and inject genetic material inside with directions to assemble new viral particles, which are all released when the bacterial cell lyses, or bursts open.

Where are all of these bacteria-busting viruses hiding? Phages are found wherever bacteria are present. From the bottom of the ocean to lakes and streams, deep in the soil, and even water treatment plants, phages are just about everywhere. Unpolluted freshwater has about 10 million phages in just one drop.(2) Phages will also hitch a ride on plants and animals, and that’s right, humans, too. But don’t worry, phages are harmless to humans. They are only interested in snacking on bacteria.

Over the past decade, the human microbiome (all the bacteria, viruses, fungi, and archaea in and on the body) has been a growing field of research. And along the way, we have learned about the human “phageome,” the collection of phages that regularly reside on people. Researchers have detected phages in healthy individuals’ gut, mouth, lungs, urinary tract, and skin. In fact, one key to good health may be a healthy phageome.(3) Disruptions of this set of common phages shared by healthy individuals are associated with obesity, bowel disorders, acne, and other diseases.

Phage discovery: A brief history

Félix d’Hérelle, a French-Canadian microbiologist, first published reports about the bacteria-killing viruses for which he coined the term ‘bacteriophage’ in 1917. He quickly recognized that phages might be clinically valuable to control bacterial growth and prevent deadly infections. In the first documented use of phage therapeutically, d’Hérelle administered a phage concoction to four sick children at a hospital in Paris, successfully treating them for dysentery in 1919. Throughout the early 20th century, phage therapy centers and commercial phage production plants opened across Europe and India, treating people for dysentery, cholera, bubonic plague, and other bacterial illnesses. Despite early successes, phage therapy fell out of popularity in Western medicine as antibiotics became more readily available. Notably, phage-based research and treatments continued unabated in some regions, including the former Soviet Union and Poland.(4)

 

Rediscovering the power of phage

Today, the popularity of phages is rising once again in Western medicine. With antibiotic-resistant bacteria becoming a global health crisis, doctors are again turning to bacteriophages to handle deadly bacteria that don’t respond to other measures.(5)

Phages became classified as Generally Recognized as Safe (GRAS) by the US Food and Drug Administration (FDA) for food safety in the early 2000s. The food industry now commonly uses phage sprays to prevent bacterial contamination. Phage formulations applied to food packaging and the food itself (including meat, dairy, fruits, and vegetables) control the growth of foodborne pathogens, including Salmonella spp., Listeria monocytogenes, and Escherichia coli, to name a few. The use of these commercial phage preparations keeps food fresh from farm to fork and curbs the occurrence of foodborne illnesses.

Clinically, phages have proven to be life-saving when antibiotics fall short. In 2016, with emergency use authorization from the FDA, Tom Patterson became one of the first patients in the US to receive phage therapy after his deadly infection proved resistant to all known antibiotics. He quickly bounced back from his illness after receiving a series of custom phage cocktails intravenously. While systemic use of phages is still only done on a case-by-case basis in the US, physicians in Russia, Georgia, and Poland regularly administer phages to manage uncontrollable superbugs found in infections. These successes over the past century support bacteriophages as an essential therapeutic agent for controlling bacterial growth moving forward.

Throughout the Phage Philes, we will investigate many topics related to bacteriophages.

  • Examine the details of phage biology: What are phages? How do they infect bacteria? How can we be sure they don’t infect humans?

  • Explore applications for phages: How have phages been used therapeutically in humans? What else can they help us with?

  • Compare phages with other antibacterial measures: What are the benefits of phages? Could they really replace antibiotics?

  • Take a deep dive into the human phageome: Where do people encounter phage? How do phages interact with humans and their microbiome?

Want to learn more about bacteriophages? Check out these sources:

1 Wittebole, X., De Roock, S. & Opal, S. M. A historical overview of bacteriophage therapy as an alternative to         antibiotics for the treatment of bacterial pathogens. Virulence 5, 226-235, doi:10.4161/viru.25991 (2014).

2 Bergh, O., Børsheim, K. Y., Bratbak, G. & Heldal, M. High abundance of viruses found in aquatic environments.   Nature 340, 467-468, doi:10.1038/340467a0 (1989).

3 Zárate, S., Taboada, B., Yocupicio-Monroy, M. & Arias, C. F. Human Virome. Archives of Medical Research 48,  701-716, doi:https://doi.org/10.1016/j.arcmed.2018.01.005 (2017).

4 Sulakvelidze, A., Alavidze, Z. & Morris, J. G., Jr. Bacteriophage therapy. Antimicrob Agents Chemother 45, 649-659, doi:10.1128/aac.45.3.649-659.2001 (2001).

5 Kortright, K. E., Chan, B. K., Koff, J. L. & Turner, P. E. Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria. Cell Host & Microbe 25, 219-232, doi:10.1016/j.chom.2019.01.014 (2019).

Part 2

Phage Philes: Part 2

Phage Biology: The Life of Phage

 

Living in a phage-filled world

Bacteriophages, viruses that infect and kill bacteria, are the most numerous entities on the planet. Yet, despite how abundant and prevalent phages are, these tiny bacteria-parasitizing virions weren’t discovered until the early 1900s. Since then, we have learned a lot about the fundamentals of phages, like what they are and how they work. To this day, scientists continue to explore the immense diversity of phages.

Mysterious antibacterial activity

At the turn of the 20th century, scientists initially noticed bacteriophages for their ability to kill bacteria, but it wasn’t immediately clear what they had found. They recorded cases where certain water or fecal filtrates could inhibit the growth of bacteria, which is now referred to as the “bacteriophage phenomenon.” Early hypotheses debated whether it was a protein, a chemical, a virus, or some other substance responsible for the observed bacterial death. Without knowing exactly what he was working with, Félix d’Hérelle, a French-Canadian microbiologist, called the mysterious bacteria-eating microbes “bacteriophages,” a name that stuck.

Over the following decades, researchers continued to characterize phage behavior and applications. Finally, in 1940, German scientists had a powerful enough microscope to see what was eliminating bacteria—these tiny, peculiar bacteriophage particles. With time, the phage photos circulated among scientific communities across the globe.

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Closer Look

Taking a closer look at phages
Like other viruses, phages are not cellular. Instead, they have genetic material inside a protein shell called a capsid head.

 

Phages have immense biodiversity. They are typically categorized based on the type of genetic material they have and their morphology (how they appear under a microscope). 

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Depending on the phage type, the genetic information can be deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), either single or double-stranded. To date, a majority of characterized phages have DNA genomes.

 

Over 96% of known phages are Caudovirales, or “tailed viruses.”(1) Giving phages the look of a lunar lander, the tail is an appendage stemming off the capsid head capped with little leg-like projections called tail fibers.(2) The most studied families of tailed phages include Myo-, Sipho-, and Podoviridae types with varying tail morphology. Myoviridae have a long contractile tail, while Siphoviridae and Podoviridae have noncontractile tails that are long and short, respectively. (What type of phage is shown under the microscope in the image above? Keep reading to find out!)

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The capsid head of tailed phages usually appears spherical at a glance, but many are actually icosahedral shaped with 20 triangular faces. Notably, capsid structures are often symmetrical, with repeating protein subunits on each side. These highly ordered protein shells house and protect the phage’s genetic information. In fact, DNA packed tightly inside can actually expand the capsid a bit.

Other phages like Corticoviridae and Microviridae have semi-spherical capsids without any tail. Filamentous phages (Inoviridae) are also tailless but with a long wormy-shaped capsid. Interestingly, fifteen types of non-tailed phages are known, yet they make up only 4% of inspected phages.1 It is still unclear to scientists why this might be, but they wonder if tailed phages are most easily recognized under the microscope or if the tail has some major benefits for the phages (more below on what the tail is for). 

Over the past 80 years, scientists have primarily relied on morphological traits to classify phages. However, in recent years, advancements in DNA sequencing technology have allowed for an even closer inspection of phages and more detailed characterization. Genetic analysis has revealed a rather complicated web of evolutionary relationships among phages. Interestingly, even phages that appear similar at a glance can have wildly different genetic markers, suggesting they are not as closely related as initially thought. Scientists continue to refine the classification system of phages as more are discovered and investigated. 

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Enter Phage

Enter phage: how bacteria get infected
Like other viruses, phages are non-living entities that cannot reproduce independently; they depend on bacterial hosts to replicate and survive. To expand their populations, phages must infect bacteria.(3)


Phages are very particular about what bacterium they will parasitize. Each phage type has a narrow host preference, usually only select species or even strains of bacteria. For example, one of the most well-characterized phages, called T4, exclusively infects Escherichia coli. 


To achieve this remarkable specificity, bacteriophages use an elaborate “lock and key” recognition system to identify bacterial cells of interest. That is, a phage recognizes and binds the target microbe through specific molecules that coat the bacterium. 


Various proteins and other molecules on the outside of the bacterium make it recognizable to its phage predator including polysaccharides, outer membrane proteins, and components of flagella and pili structures, to name just a few. 


To detect and discern their prey, phages use so-called receptor binding proteins (RBPs) at the phage’s tail-end. Some tails have intricate structures at the tip, including baseplates, spikes, and fibers to guide specific binding to the bacterial host.


In fact, host recognition is a complex process where many tail proteins interact with multiple different surface molecules on the bacteria. For example, Escherichia coli is targeted through lipopolysaccharide (LPS) and OmpC porin proteins by the T4 phage.(4) On the other hand, a siphophage called iEPS5 attaches to Salmonella by recognizing FliC and FljB proteins of the bacterium’s flagellum propeller.(5) These redundant mechanisms ensure the correct bacterium is selected and infected to replicate the phage successfully. 


Once a phage finds and attaches to a suitable bacterial cell, the infection process continues. Enzymes on the tip of the phage’s tail eat away at the exterior of the bacteria. These same types of enzymes allow phages to degrade and infiltrate biofilms, the tough tight-knit bacterial colonies that can contribute to antibiotic resistance. 


After digging through the outside layer, phages inject their viral genetic material into a bacterial cell. In addition to facilitating recognition, the tail is also a conduit connecting the virus to the target microbe. The phage’s genetic material passes through the tubular tail and enters the bacterium. 

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To kill or not to kill: lytic or lysogenic phages

What happens once a phage has injected its DNA (or RNA) into a bacterium? Very rapidly, the bacterial cell turns into a phage manufacturing plant. The cellular machinery is hijacked to produce new phage components that quickly assemble to form new phages. When they get the signal, the fresh phages burst the bacterium. Phage multiplication happens in minutes to hours, and over a thousand viral particles spew from the dead bacterium. Other bacteria in the immediate area are now at risk of being infected next. 

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Virulent phages reproduce through this deadly process that is known as the “lytic cycle.” Along with generating many new phage particles, the lytic cycle also breaks open (or lyses) the cell, resulting in the death of that bacterium. Notably, therapeutic applications of phages, commonly referred to as “phage therapy,” depend on the lytic cycle to rapidly kill infected bacteria.

For this reason, so-called temperate phages that follow the “lysogenic cycle” are not typically useful for antibacterial applications. Instead of killing microbes, temperate phages will infect bacteria and enter a dormant state. The genetic material quietly integrates into the bacterial genome instead of starting phage replication. In most cases, the bacterial cell is not affected by the infection of a temperate phage and will continue to grow as usual. The dormant phage genes may eventually reactivate in certain circumstances to produce phage particles.

Key points:

  • Phages have immense biodiversity. Scientists continue to discover and investigate new phages.

  • Phages are highly specific with what cells they will parasitize. They don’t recognize or infect human cells and are very selective in the species or strain of bacteria they will choose.

  • Virulent phages reproduce through the lytic cycle that rapidly kills the bacteria. In the lysogenic cycle, temperate phages go dormant and don’t usually kill the bacteria.

Still wondering? The phages shown under the microscope are Siphoviridae! These are the long, non-contractile-tailed bacteriophages found in DermaPhage® CA .

To learn more about the history and possibilities of phage therapy using lytic phages, see the next post.

 

References

1 Ackermann, H. W. 5500 Phages examined in the electron microscope. Archives of Virology 152, 227-243, doi:10.1007/s00705-006-0849-1 (2007).

2 Dion, M. B., Oechslin, F. & Moineau, S. Phage diversity, genomics and phylogeny. Nature Reviews Microbiology 18, 125-138, doi:10.1038/s41579-019-0311-5 (2020).

3 Stone, E., Campbell, K., Grant, I. & McAuliffe, O. Understanding and Exploiting Phage-Host Interactions. Viruses 11, doi:10.3390/v11060567 (2019).

4 Washizaki, A., Yonesaki, T. & Otsuka, Y. Characterization of the interactions between Escherichia coli receptors, LPS and OmpC, and bacteriophage T4 long tail fibers. Microbiologyopen 5, 1003-1015, doi:10.1002/mbo3.384 (2016).

5 Choi, Y., Shin, H., Lee, J. H. & Ryu, S. Identification and characterization of a novel flagellum-dependent Salmonella-infecting bacteriophage, iEPS5. Appl Environ Microbiol 79, 4829-4837, doi:10.1128/aem.00706-13 (2013).

Part 3

Phage Philes: Part 3

A century-long story: Using bacteriophages to control ‘bad’ bacteria

Living in a phage-filled world

The utility of bacteriophages was almost immediately obvious upon their discovery about a century ago. While working in Paris at the Institut Pasteur, Félix d’Hérelle stumbled upon bacteriophages after noticing that certain microbial filtrates prevented bacterial growth. Referred to simply as phages, these tiny bacteria-killing viruses were first put to work in 1919 when a phage-based treatment was administered to four sick children at l'Hôpital des Enfants-Malades.(1) All of the kids bounced back from bacterial dysentery after receiving what has since been called “phage therapy.”

Over the coming decades, physicians worldwide explored and implemented the clinical use of phages. Phages treated patients with dysentery, cholera, and other bacterial ailments, and phage preparations became commercially available in France and the US. But as the Second World War ended and antibiotics became readily available, phages were forgotten by most. Today, as antibiotics fail against resistant bacteria, science has pivoted the spotlight back to phages to curb unwanted and often harmful bacterial growth.

 

Early enthusiasm for phage therapy

In the years following their discovery, applications of phage quickly moved from treating chickens with Salmonella gallinarum to healing children infected with Shigella dysentriae. Multiple phage-focused foundations were formed to research and develop phage therapies, including the George Eliava Institute of Bacteriophage, Microbiology, and Virology (IBMV) in Tbilisi, Georgia.

Across the globe, the successful use of phages to treat and prevent human diseases was widespread. Beginning in the mid-1920s, phage against Shigella dysentriae was produced in Brazil and distributed across Latin America to prevent and treat cases of dysentery.(2) In India, clinical trials implementing Vibrio cholerae-targeting phage therapy reduced cholera mortality from 62% to less than 10%.(3) With this success, anticholera phage was also introduced to Indian drinking wells to reduce infection rates during outbreaks.

Phages fall out of favor

Along with the early enthusiasm for phage came some criticism. Some concerns stemmed from the reported variability of efficacy. For example, a phage preparation successfully reduced the bacterial levels of typhoid patients in 1923. However, reports one year later found that the same phage was ineffective in another population of patients.(4) Phage enthusiasts, including d’Hérelle, acknowledged these inconsistencies. They offered possible explanations, including phage specificity obstacles, where the correct phages were not identified and applied. Early practices also saw issues with unreliable manufacturing processes and mishandling phage preparations that rendered phage inactive.

Today, studies are better designed to consider both efficacy and safety for practical use. More recent research has supported remarkable advancements in the commercial manufacturing and distribution of phages. At the same time, increased screening abilities now allow more rapid identification of the problematic bacteria and the desired phages for each specific application.

Despite our current clarity on these issues, phages’ perceived shortcomings at the time discouraged Western physicians from using phage therapy. Easier to produce and deliver, antibiotic compounds became the preferred intervention to clear bacterial infections. The introduction of penicillin in 1942 began the “golden age” of antibiotics, with over 40 antibacterial compounds discovered and implemented over the next 30 years.

Phage wins in Eastern Europe

Despite losing interest in western countries, scientists and physicians in Georgia, Poland, and the former Soviet Union pushed on. The study of phage biology and therapeutics went unabated in Eastern Europe.

 

Researchers at dedicated phage laboratories, including the Eliava IBMV and the Hirszfeld Institute of Immunology and Experimental Therapy in Wroclaw, Poland, explored phage biology and conducted large-scale clinical trials to further demonstrate the efficacy of phage when properly applied.

 

For example, throughout the 1960s, over 30,000 children under the age of 7 participated in a trial testing phages’ ability to prevent bacterial dysentery. These prophylactic experiments found that the incidence of dysentery was 3.8 times lower in kids who were getting phage treatment.1 Another large trial saw a 5-fold decrease in typhoid in individuals receiving phage compared to those who were not.(5)

 

While Eastern European researchers made sizeable advancements in phage research throughout the midcentury, the news was slow to travel. Many phage findings were published in small, non-English journals that were not widely distributed. These barriers, combined with residual political tensions from World War II, significantly dampened interest in phages for antibacterial applications in some regions of the world.(6)

Phage History
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A return to the West

Two researchers, Smith and Huggins, published data throughout the 1980s that addressed common criticisms of bacteriophages. By demonstrating phages’ safety and efficacy, these studies drew attention and began to reignite the potential for phages in Western countries.

These studies addressed concerns about phage stability and delivery. For example, Smith realized that some ingested phages were degraded by the stomach’s acidic conditions and discovered that delivering phages with calcium carbonate helped to preserve phage activity.(7) Further, Smith and Huggins demonstrated that implementing mixtures of multiple different phages, so-called “multi-phage cocktails,” assuaged any worry of phage resistance.(8)

Ultimately, Huggins’ research revealed that the early perceived criticisms of phage therapy were unfounded or less concerning than initially thought, propelling new approaches to phage therapy.

Today’s expanding relevance of phages

Today, it is becoming more widely recognized that phages are remarkable tools for knocking down bacterial growth in a targeted way.

Russia and other eastern European countries continue to use phage cocktails in medicine to treat a wide variety of infections involving respiratory, gastrointestinal, dermatological, and urological diseases and beyond.

The medical use of phage-based medical treatments continues to be developed in the United States. Namely, the Center for Innovative Phage Applications and Therapeutics (IPATH) at the University of California San Diego became North America's first dedicated phage therapy center. Through institutions like these, phages are used in emergency, life-threatening cases when other interventions prove futile via the Food and Drug Administration’s (FDA) compassionate use program. For instance, the success story of Tom Patterson made headlines in 2017 when his antibiotic-resistant infection cleared after a phage intervention.(9)

Phage therapy is also being further evaluated with numerous clinical trials to demonstrate the efficacy and safety of phages systematically. For example, the first phase I clinical trial in the US tested and confirmed the effectiveness of phage preparations in treating ear infections caused by antibiotic-resistant Pseudomonas aeruginosa.(10) Ongoing clinical trials at Yale University are administering phage nebulizers to cystic fibrosis patients. 


The antimicrobial benefits of phages are leveraged in industries beyond the medical field. Microbes are being kept at bay in the food industry by spraying processing equipment, packaging, and the food itself with phage cocktails, with a stamp of approval from the FDA.(11) The bactericidal properties of phages are also put to work in other industries, including skincare, biotechnology, agriculture, veterinary medicine, and environmental protection and remediation.(12)


In 2022, Biocogent LLC announced the launch of DermaPhage® CA, the first natural active skincare ingredient of its kind for blemish-prone skin. DermaPhage CA is a fast-acting bacteriophage cocktail targeting Cutibacterium acnes, a microbial culprit of blemish flare-ups and skin inflammation. The three unique bacteriophages contained in DermaPhage CA demonstrate optimum safety and efficacy for use in facial and body care products, sprayable formulas for linens, or laundry detergents and additives to diminish the growth of C. acnes on the skin.


In fact, Biocogent is launching an entire DermaPhage® category of natural skincare actives. Leveraging established expertise in research and manufacturing, Biocogent will continue to deliver innovative bacteriophage-based products to control problematic bacteria associated with unhealthy skin conditions.

 

A bright future for phages
With a dynamic past, phages have now become one of the best-studied microbes with an extensive body of scientific literature.(13) Research has built a foundational understanding of phage biology to inform many aspects of applying phage to bacteria-based issues across society.


Ultimately, the time has come for bacteriophages. Once-controlled bacteria are becoming dangerous again as antibiotic resistance is on the rise, and the development of new antibiotic compounds has slowed to a near halt. As robust bacteria-killing viruses, phages are a promising tool to conquer these problematic bacteria.

References and additional readings:

1 Sulakvelidze, A., Alavidze, Z. & Morris, J. G., Jr. Bacteriophage therapy. Antimicrob Agents Chemother 45, 649-659, doi:10.1128/aac.45.3.649-659.2001 (2001).

2 Almeida, G. M. F. & Sundberg, L. R. The forgotten tale of Brazilian phage therapy. Lancet Infect Dis 20, e90-e101, doi:10.1016/s1473-3099(20)30060-8 (2020).

3 d'Herelle, F., Lahiri, M. N. & Malone, R. H. Studies on Asiatic Cholera.  (Calcutta, 1930).

4 Smith, J. The Bacteriophage In The Treatment Of Typhoid Fever. British Medical Journal 2, 47-49, doi:10.1136/bmj.2.3315.47 (1924).

5 Lin, D. M., Koskella, B. & Lin, H. C. Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World J Gastrointest Pharmacol Ther 8, 162-173, doi:10.4292/wjgpt.v8.i3.162 (2017).

6 Summers, W. C. The strange history of phage therapy. Bacteriophage 2, 130-133, doi:10.4161/bact.20757 (2012).

7 Smith, H. W., Huggins, M. B. & Shaw, K. M. Factors influencing the survival and multiplication of bacteriophages in calves and in their environment. J Gen Microbiol 133, 1127-1135, doi:10.1099/00221287-133-5-1127 (1987).

8 Smith, H. W. & Huggins, M. B. Effectiveness of phages in treating experimental Escherichia coli diarrhoea in calves, piglets and lambs. J Gen Microbiol 129, 2659-2675, doi:10.1099/00221287-129-8-2659 (1983).

9 Schooley, R. T. et al. Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Antimicrob Agents Chemother 61, doi:10.1128/aac.00954-17 (2017).

10 Wright, A., Hawkins, C. H., Anggård, E. E. & Harper, D. R. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol 34, 349-357, doi:10.1111/j.1749-4486.2009.01973.x (2009).

11 Moye, Z. D., Woolston, J. & Sulakvelidze, A. Bacteriophage Applications for Food Production and Processing. Viruses 10, doi:10.3390/v10040205 (2018).

12 Sohail, H. A. et al. Bacteriophages: Emerging Applications in Medicine, Food, and Biotechnology. PHAGE 1, 75-82, doi:10.1089/phage.2020.29004.has (2020).

13 Wittebole, X., De Roock, S. & Opal, S. M. A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence 5, 226-235, doi:10.4161/viru.25991 (2014).

Part 4

Phage Philes: Part Four
Turning a new page with bacteriophage
Chapter 1: Introductions

 

What are phages?
Phages (short for bacteriophages) are highly specialized microbes that target and destroy bacteria in a highly specific manner. 

 

As the most abundant organism on the planet, it is no surprise that phages naturally inhabit the human body. On our skin, an average of one million phages can be found per square centimeter.(1) Diverse phage communities can be found adhered to our skin as well as mucus membranes (such as those found in the nose, mouth, eyes, and digestive tract). These large populations of bacteria-slaying microorganisms provide protection from invaders as part of the body’s natural defense system.(2)
 

Phages are a lesser-known agent for controlling microbial growth. As nature’s bactericidal ninjas, phages have been implemented against harmful bacteria in various parts of the world for over 100 years.

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Phages applied topically can help restore balance and improve the skin’s healthy appearance.

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What are antibiotics?

The term “antibiotics” refers to chemical compounds that can be used in humans, animals, or plants to stifle unwanted bacterial growth.


Some antibiotic compounds are derived from natural sources (like fungi or bacteria), with further innovations leading to semi-synthetic and synthetic variations as well. Different classes of antibiotics work in various ways to interfere with the way bacteria grow and replicate, ultimately getting rid of them.

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On the skin, topical antibiotics can be used for dermatological issues such as impetigo, acne, and dermatitis.

The first antibiotics became commercially available in the 1940s, followed by a plethora of compounds over the next 80 years. Throughout the 20th century, applications for antibacterial compounds expanded to include human medicine as well as animal and plant agriculture, with up to 150,000 tons (about 150 million kilograms) of antibiotics used globally each year.(3)


Overall, antibiotics are up against major obstacles as the incidence of antimicrobial resistance is on the rise while the rate of discovery continues to decline. 

Chapter 2: Rates of Resistance

 

Rising rates of antibiotic resistance

Bacteria’s capacity to dodge antibiotics, known as antibiotic resistance, has become an “urgent global risk,” according to the United Nations General Assembly.3 The rates of antibiotic resistance are expanding, along with the variety of microbes that carry resistance. Between the 1980s and the 2000s, the rate of antibiotic resistance in Cutibacterium acnes increased by nearly 40%(4) and continues to rise in populations throughout the world. Vancomycin, considered an antibiotic of “last resort,” was on the market for over 30 years before instances of resistance were reported. Unfortunately, the prevalence rose rapidly, increasing by over 25-fold in just 5 years.(5) 
 

Bacteria can become resistant to antibiotic compounds in many different ways. In some cases, the microbes pass around “resistance genes,” pieces of DNA encoding tools against antibiotic compounds that ultimately allow bacteria to circumvent death. In particular, a resistance gene might prevent antibiotics from infiltrating the bacterial cell, while another could give bacteria the ability to destroy the compound before succumbing to the intended lethal effects. 

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Many factors contribute to the rapid rate of resistance we are seeing today, including the overuse of antibiotics, which encourage the transfer of resistance genes among bacteria as well as the formation of impenetrable biofilms. With excessive use of these chemicals, bacterial antibiotic resistance continues to become an increasing concern.

 

Phage so good you just “can’t resist”
Considering the crisis of antibiotic resistance, the possibility of phage resistance becomes a question worth considering. Thankfully, the threat of resistance occurring in phages the way it has with antibiotics is less likely for several reasons.


Firstly, phages are hyper-specific in selecting and attacking their target microbe, rather than being indiscriminately antibacterial as antibiotics tend to be. So, while antibiotics run the risk of driving resistance in any bacterial species that are present, a phage artfully targets only its species of interest while the rest of the microbes remain unaware and unaffected.


Additionally, the way that phages operate to destroy bacteria is fundamentally different from the mechanisms at play with antibiotic compounds. Rather than focusing on jamming up only one specific bacterial process as antibiotics often do, phages hijack multiple essential processes in parallel. Bacteria may craftily dance around the one particular method an antibiotic is using (i.e. resistance), but this is not so easy when phages wreak havoc throughout the entire cell.

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Phages surgically pinpoint and effectively eradicate their target species of bacteria, as compared to more bumbling broad-spectrum antibiotics, making phages much less susceptible to the widespread resistance phenomenon that has sabotaged antibiotic efficacy.

Notably, resistance to phage can and does occur, but it looks a lot different than antibiotic resistance. A major benefit of bacteriophages is their extensive “experience” overcoming the resistance efforts of bacteria. In fact, the evolutionary arms race between phage and their bacterial targets has been ongoing for the past 3 billion years or so, since phages came into existence. So, while a sly bacterium may invent a clever tactic to thwart phage attacks, phages will continue to adapt and prevail over their microbial prey—something that antimicrobial compounds are incapable of. 


At the same time, experts deploying phages are actively taking additional steps to assuage concerns about resistance. For instance, methods often use mixtures containing multiple phage types aimed at the culprit bacteria, often referred to as “phage cocktails,” since the chance of a microbe simultaneously developing resistance to numerous phages is much less likely. 

Chapter 3: Rates of Discovery

 

Buckets of phage

Novel phage discovery can look as simple as a person with a bucket. Phage hunters (like Dr. Benjamin Chan at Yale University) sample water treatment facilities and other waterways to track down the phages they need.(6) 

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Freshwater can have over 10 million bacteriophages in just one drop.

Phages are found where ever bacteria are present. There are more phages on the planet than there are stars in the universe (ten million times as many!). With their astonishing abundance plus extensive genetic diversity, it is no surprise that scientists are often able to find what they are looking for. Notably, phages can be naturally sourced without significant environmental impact. 


Once phages are collected, continuously advancing molecular biology techniques allow for rapid screening and identification of the desired phage. The generation of “phage libraries” with carefully characterized phages has proven useful for organizing the huge number of diverse bacteriophages being gathered.

 

The antibiotic pipeline runs dry
After the introduction of the first compounds in the 1940s, a wide variety of antibiotics continued to be discovered as research boomed throughout the 1960s. However, the golden era of discovery soon lost steam, and many pharmaceutical screening efforts began to come up empty-handed. 

 

The discovery rate of antibiotics started to stumble and has now slowed to a crawl. Between 1983 and 1987, 16 new pharmaceutical antibiotics became available in the US. However, only two new antibiotic compounds came to market during the same number of years spanning from 2008 to 2012.(7) 
 

Chapter 4: Precision

 

A meticulous microbe

Mounting scientific evidence supports the importance of a balanced microbiome for human health. Beneficial microbes reside in our guts, on our skin, and throughout the body to contribute to our overall homeostasis.(8,9) A loss of microbial balance, known as dysbiosis, contributes to a variety of disorders, such as diabetes, celiac disease, and eczema.(10)


Phage’s carefully focused attacks help to reduce the disruption of non-target bacteria, preserving the balance of the natural microbiome. Thankfully, phages have a notoriously narrow host range, typically honing their sights on only one bacterial species. This allows the utilization of specific phages to selectively target the pathogenic microorganisms only. 


On the other hand, antibiotics are quite general in their bactericidal tendencies and can cause collateral damage to the rest of the microbiome. Antibiotic compounds do not distinguish between the problematic bacteria and the resident bacteria that we don’t want to disturb. 
 

Chapter 5: The battle with biofilms

 

Busting biofilms with bacteriophage

Individual bacterial cells can work together to form complex, robust communities known as biofilms. Some bacteria produce elaborately layered biofilms composed of sticky, secreted polysaccharides, proteins, and DNA, that help them to adhere to tissues and protect the embedded microbes.
 

Bacteria in a biofilm tend to cause more trouble than their planktonic (free-floating) counterparts. For example, the materials of Cutibacterium acnes biofilm, combined with sebum and shedding dead skin cells, can clog pores to incite blemish formation and associated inflammation.(11) In fact, scientific studies have found that C. acnes biofilm is more pronounced within the pilosebaceous glands of blemished skin as compared with healthy skin.(12) 

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Many antibiotics cannot effectively infiltrate biofilms to kill the microbes inside, further contributing to antibiotic resistance.(13) 


Fortunately, many phages can infiltrate and destroy problematic bacterial biofilms. Specifically, these phages express biofilm-degrading enzymes that can break down existing biofilms and impede the formation of new ones.

Epilogue: Phages for the skin

 

The power of bacteriophages has been recognized. Biocogent has developed DermaPhage® CA to utilize all of phages’ potential for the improvement of blemish-prone skin. To learn more, visit the DermaPhage CA page.

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References & additional resources:
1 Zárate, S., Taboada, B., Yocupicio-Monroy, M. & Arias, C. F. Human Virome. Archives of Medical Research 48, 701-716, doi:https://doi.org/10.1016/j.arcmed.2018.01.005 (2017).
2 Barr, J. J. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc Natl Acad Sci U S A 110, 10771-10776, doi:10.1073/pnas.1305923110 (2013).
3 Lin, D. M., Koskella, B. & Lin, H. C. Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World J Gastrointest Pharmacol Ther 8, 162-173, doi:10.4292/wjgpt.v8.i3.162 (2017).
4 Coates, P. et al. Prevalence of antibiotic-resistant propionibacteria on the skin of acne patients: 10-year surveillance data and snapshot distribution study. Br J Dermatol 146, 840-848, doi:10.1046/j.1365-2133.2002.04690.x (2002).
5 Dodds, D. R. Antibiotic resistance: A current epilogue. Biochem Pharmacol 134, 139-146, doi:10.1016/j.bcp.2016.12.005 (2017).
6 Chan, B. K. et al. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health 2018, 60-66, doi:10.1093/emph/eoy005 (2018).
7 Boucher, H. W. et al. 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis 56, 1685-1694, doi:10.1093/cid/cit152 (2013).
8 Flowers, L. & Grice, E. A. The Skin Microbiota: Balancing Risk and Reward. Cell Host Microbe 28, 190-200, doi:10.1016/j.chom.2020.06.017 (2020).
9 La Flamme, A. C. & Milling, S. Immunological partners: the gut microbiome in homeostasis and disease. Immunology 161, 1-3, doi:10.1111/imm.13247 (2020).
10 Schippa, S. & Conte, M. P. Dysbiotic events in gut microbiota: impact on human health. Nutrients 6, 5786-5805, doi:10.3390/nu6125786 (2014).
11 Burkhart, C. G. & Burkhart, C. N. Expanding the microcomedone theory and acne therapeutics: Propionibacterium acnes biofilm produces biological glue that holds corneocytes together to form plug. J Am Acad Dermatol 57, 722-724, doi:10.1016/j.jaad.2007.05.013 (2007).
12 Jahns, A. C. et al. An increased incidence of Propionibacterium acnes biofilms in acne vulgaris: a case-control study. Br J Dermatol 167, 50-58, doi:10.1111/j.1365-2133.2012.10897.x (2012).
13 Flemming, H. C. et al. Biofilms: an emergent form of bacterial life. Nat Rev Microbiol 14, 563-575, doi:10.1038/nrmicro.2016.94 (2016).

Part5

Phage Philes: Part Five

Bacteriophage in the skin microbiome

Bacteriophages are the most numerous entities on the planet. From high in the sky to the bottom of the ocean, phages are everywhere. (1) Phages surround us — in the air, water, and soil. As such, it should be no surprise that we have phages throughout our bodies as essential microbiome members.
 

Your microbial “other half”

You have probably heard about the human microbiome – the collection of bacteria, fungi, archaea, and viruses that call your body home. Influenced by a person’s genetics, age, environment, and lifestyle, everyone has a bustling microbiome with billions of microbes. These microorganisms inhabit the entire body, including the digestive system (mouth, stomach, intestines), the respiratory tract (nose, lungs), eyes, ears, blood, skin, and more. In total, it is estimated that nearly HALF of the cells in your body are not human; microbes are the other half of you. (2,3)

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The skin as an ecosystem

The skin’s primary function is to act as a physical barrier from the outside world. In addition to keeping water in and harmful substances out, the skin is also a complex ecosystem with microbial life across its entirety, including individuals from 200 genera from 19 different phyla. (5)


A mixture of microbes occupies the skin, creating a patchwork quilt of diverse microbial populations that wraps the body’s surface. The largest organ with nearly 25 square meters of surface area, the skin is a vast and varied environment for microbes to occupy. The outermost stratum corneum is decorated with appendage structures, such as hair follicles, sebaceous glands, and sweat glands, that can all provide refuge for your microbiota.  

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The types of microbes on the skin vary depending on the area’s unique characteristics or biogeography. (4,5) For example, sebum-rich areas of the forehead harbor oil-loving Cutibacterium and Staphylococcus bacterial species and Malassezia fungus. Proteobacteria and Flavobacteriales prefer dry areas (such as the inner forearm or palm), while Corynebacterium and some Staphylococcus species live in moist environments (armpits and nostrils). Interestingly, dry sites generally have the widest diversity of microorganisms. Sebaceous sites on the face tend to be very stable, while the hands and feet seem to have the most dynamic microbial populations. Each diverse microenvironment on the skin provides its microbial constituents with conditions to thrive. 

Getting to know the “virome”

While bacteria tend to get the most attention, viruses are also a significant component of the human microbiota, known as the “virome”. (6) Over the past decade or so, the methods to detect viruses have advanced, facilitating the characterization of the human virome. Viruses seem to inhabit every location on the body, from the cerebrospinal fluid surrounding the brain to the skin’s surface. (3)


Remarkably, very few viruses found throughout the human body can infect human cells (less than 10%). (7) Instead, the human virome is dominated by phages, the prokaryotic viruses that infect bacteria and other nonhuman cells.

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Caudovirales (tailed phages) are most common on the skin, accounting for over 50% of viruses, and Microviridae (non­tailed phages) are also numerous. (3,6,9) A core collection of phages is nearly universal on the skin, including phages targeting Propionibacterium, Staphylococcus, and Streptococcus. (9)

What do phages want from us?

Our body serves as a “hunting ground” where phages prey on their preferred strains of bacteria. Researchers have found that phages are distributed on the skin based on the bacteria in each environment. (6,9) For example, the phages that target Cutibacterium (previously known as Propionibacterium) are significantly more abundant at the sebaceous sites that Cutibacterium bacteria love. (6) 


What’s more, phages help to shape microbial communities through their predation. (6,10,11) Scientists have discovered an inverse relationship between phages and bacteria, meaning that the more Cutibacterium-targeting phages at a location, the fewer Cutibacterium bacteria there. (9) This naturally occurring antagonism between the lytic phages and their host bacteria demonstrates the phages’ ability to impact the skin’s microbial content.

More than microbial hitchhikers

A growing body of scientific evidence supports the microbiome as a fundamental component of human health. A balanced, healthy microbiome contributes to overall wellness. For example, the cutaneous microbiota helps contribute to the skin’s natural processes and characteristics. Specifically, metabolically active microbes secrete enzymes necessary for desquamation and stratum corneum renewal. The microorganisms also produce free fatty acids that help maintain the skin’s pH. Additionally, the skin microbiome has been found to interface with our immune system to promote pathogen defense, control inflammation, and train adaptive immunity.

A balancing act

The microbes on our skin form intricate communities that promote and preserve diversity. Various mechanisms are in place to ensure that no species dominate the others.


In cases of infection or other skin disorders, some resident microbes can become pathogenic and contribute to excessive inflammation, tissue damage, and other painful symptoms. This dysbiosis plays a role in several cutaneous disorders, including acne, atopic dermatitis (eczema), psoriasis, rosacea, dandruff, and chronic wounds.


Here we explore examples of dysbiosis, highlighting the intricate interactions that are fundamental for the stability of the microbiome. 

Act I: Blemished skin lacking some phages

While Cutibacterium acnes is a predominant resident species on all skin, blemish-prone skin is often overpopulated with “acneic” C. acnes strains that drive excessive production of immune-stimulating molecules (such as porphyrin compounds associated with acne severity). (13-15) In parallel, active lytic C. acnes phages are sometimes diminished on acne patients’ skin. (16) Notably, reintroducing C. acnes-targeting bacteriophages can help to reestablish homeostasis and reduce the appearance of blemishes on acne-prone skin. The C. acnes population also seems to be maintained through competitive interactions with S. epidermidis in sebaceous areas. Stable communities containing both C. acnes and S. epidermidis contribute to healthy skin with imbalances of strain diversity and relative abundance in blemished skin. (17) Taken together, C. acnes interactions illustrate the complexity of the microbiome crosstalk and its impact on skin health.

Act II: Psoriasis associated with depleted phages

Studies of psoriatic skin demonstrate the strong ties between the phage and bacterial communities on the skin. For example, scientists found that psoriatic skin has lower levels of the phages that target Acinetobacter and Pseudomonas compared to healthy skin of the same individual or other people without psoriasis. (12) Most notably, skin with fewer phages has concurrent blossoms of host bacteria with an overall loss of microbial diversity. These findings reinforce the link between a balanced microbiome and healthy skin.

References

1 Wainwright, M., Alharbi, S. & Wickramasinghe, N. C. How do microorganisms reach the stratosphere? International Journal of Astrobiology 5, 13-15 (2006). https://doi.org:10.1017/S1473550406002825
2 Sender, R., Fuchs, S. & Milo, R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLOS Biology 14, e1002533 (2016). https://doi.org:10.1371/journal.pbio.1002533
3 Liang, G. & Bushman, F. D. The human virome: assembly, composition and host interactions. Nature Reviews Microbiology 19, 514-527 (2021). https://doi.org:10.1038/s41579-021-00536-5
4 Castillo, D. E., Nanda, S. & Keri, J. E. Propionibacterium (Cutibacterium) acnes Bacteriophage Therapy in Acne: Current Evidence and Future Perspectives. Dermatol Ther (Heidelb) 9, 19-31 (2019). https://doi.org:10.1007/s13555-018-0275-9
5 Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190-1192 (2009). https://doi.org:10.1126/science.1171700
6 Hannigan, G. D. et al. The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. mBio 6, e01578-01515 (2015). https://doi.org:10.1128/mBio.01578-15
7 Shkoporov, A. N. & Hill, C. Bacteriophages of the Human Gut: The “Known Unknown” of the Microbiome. Cell Host & Microbe 25, 195-209 (2019). https://doi.org:10.1016/j.chom.2019.01.017
8 Nguyen, S. et al. Bacteriophage Transcytosis Provides a Mechanism To Cross Epithelial Cell Layers. mBio 8, e01874-01817 (2017). https://doi.org:10.1128/mBio.01874-17
9 Oh, J., Byrd, A. L., Park, M., Kong, H. H. & Segre, J. A. Temporal Stability of the Human Skin Microbiome. Cell 165, 854-866 (2016). https://doi.org:10.1016/j.cell.2016.04.008
10 Rodriguez-Brito, B. et al. Viral and microbial community dynamics in four aquatic environments. The ISME Journal 4, 739-751 (2010). https://doi.org:10.1038/ismej.2010.1
11 Brendan, J. M. B. & Lenski, R. E. Effect of Resource Enrichment on a Chemostat Community of Bacteria and Bacteriophage. Ecology 78, 2303-2315 (1997). https://doi.org:10.2307/2265893
12 Wang, H. et al. Bacteriophage of the Skin Microbiome in Patients with Psoriasis and Healthy Family Controls. J Invest Dermatol 140, 182-190.e185 (2020). https://doi.org:10.1016/j.jid.2019.05.023
13 Fitz-Gibbon, S. et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol 133, 2152-2160 (2013). https://doi.org:10.1038/jid.2013.21
14 Johnson, T., Kang, D., Barnard, E. & Li, H. Strain-level differences in porphyrin production and regulation in Propionibacterium acnes elucidate disease associations. mSphere 1 (2016). https://doi.org:10.1128/mSphere.00023-15
15 Sanford, J. A., O'Neill, A. M., Zouboulis, C. C. & Gallo, R. L. Short-Chain Fatty Acids from Cutibacterium acnes Activate Both a Canonical and Epigenetic Inflammatory Response in Human Sebocytes. J Immunol 202, 1767-1776 (2019). https://doi.org:10.4049/jimmunol.1800893
16 Jończyk-Matysiak, E. et al. Prospects of Phage Application in the Treatment of Acne Caused by Propionibacterium acnes. Frontiers in Microbiology 8 (2017). https://doi.org:10.3389/fmicb.2017.00164
17 O'Neill, A. M. & Gallo, R. L. Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris. Microbiome 6, 177 (2018). https://doi.org:10.1186/s40168-018-0558-5

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