Bacteriophage Therapy: A Promising Solution to Antibiotic Resistance

Antibiotic resistance is an emerging problem. Some have argued bacteria are developing antibiotic resistance faster than we can research, develop, test and approve new antibiotics. The World Health Organization (WHO) has warned for several years that we are on the verge of a post-antibiotic world, noting in particular a post-antibiotic world may have already arrived, as there are too few antibiotics for an increasing number of antibiotic-resistant pathogens.

One possible solution to antibiotic resistance: bacteriophages (or phages), which are viruses that infect bacteria.

The Growing Problem of Antibiotic Resistance

Bacteria begin to exhibit resistance soon after the clinical deployment of a new antibiotic (Table 1). At a high level, defining antibiotic resistance may sound simple; it basically means bacteria devise a way to survive exposure to a substance that could previously stop their growth or kill them.

Table 1:

If someone fails to complete their prescribed course of antibiotics against a bacterial infection, the heartiest and most resistant of the initial population thrive and resistance spreads (see Figure 1 and Figure 2). It’s simple Darwinian evolution: the fittest survive and their descendants take over.

Another method of fostering antibiotic resistance is the prolonged low-level exposure to antibiotics, as is currently the case when people take prescribed antibiotics and excrete the unmetabolized drugs into the sewer. Sewage treatment plants are effective at treating biological waste, but chemicals like antibiotics are released into the environment with the treated water.

Also consider: Half the antibiotics produced in the U.S. are utilized in agriculture, further exacerbating the problem of antibiotic resistance developing in the environment.

While we can refer to antibiotic resistance as a single trait bacteria can develop, there are many different mechanisms for antibiotic resistance. Figure 3 illustrates some of these examples:

• Bacteria can secrete enzymes that inactivate antibiotics (e.g., penicillinase inactivates penicillin)
• Others pump the toxic drug out of the bacterial cell, much like some chemo-resistant cancers
• Communities of bacteria can layer onto each other to form biofilms to make the collective more resistant to certain disinfectants and antibiotics
• Some bacteria have anatomical structures like cell walls, capsules, and slime layers to protect the cell from external threats

Antibiotic resistance is encoded as a genetic trait and can be transmitted between bacteria by various means (see Figure 4).

These resistance genes are commonly found on small circles of DNA called plasmids. Bacteria can exchange plasmids through conjugation, a process where bacteria connect with a sex pilus and plasmids are shared.

When cells die, their plasmids can spill into the environment for other bacteria to pick up and use in a process called transformation.

Bacteriophages can also transfer genetic traits between bacterial host cells in a process called transduction.

What Are Bacteriophages?

Bacteriophages (phages for short) are viruses that infect bacteria.

Phages deliver their genetic material into the bacteria so, when the bacteria flourishes and reproduces, the bacteria also copies the viral genome and hands it down to bacterial progeny. As such, the virus reproduces with virtually no effort (see Figure 5).

However, when the host cell is under stress, the phages hijack the bacteria’s machinery to produce as many progeny viruses as quickly as possible while killing the host (see Figure 6). The progeny viruses are released into the environment to await another host to infect. These phages don’t just benefit from the bacteria when times are good. They often carry genes to help the bacteria succeed by giving it a selective advantage, such as bacterial toxins or antibiotic resistance genes.

Bacteriophages as a Potential Alternative to Antibiotics

Discovering a new class of antibiotics is difficult – we can go decades without a new class being identified. And in our global society where germs spread faster than ever before, we already have trouble keeping up with the spread of antibiotic resistance. Many argue we need a different approach.

As scientists look for new strategies to combat antibiotic resistance, the idea of taking advantage of bacteria’s natural pathogens has become resurgent.

Phages already exist as bacteria’s natural pathogen. While developing an entirely new class of antibiotic is challenging, making minor genetic modifications to a virus or phage is something fairly easily accomplished with modern technologies.

Current Research and Future Directions

Phages are currently under study as investigational products in clinical trials targeting different bacterial maladies. Here are just a few examples of how phage therapy could improve healthcare outcomes:

• Cystic fibrosis poses a difficult challenge as a bacteria commonly found in the environment, Pseudomonas aeruginosa, forms biofilms in the lungs of patients and is a leading cause of death. Phages can be nebulized into the lungs and used to infect and kill the bacteria.
• Antibiotic-resistant E. coli is capable of causing several conditions, including potentially lethal bloodborne infections and urinary tract infections which can form biofilms on urinary catheters. Intra-venous delivery of phages has potential as therapeutics for a broad range of conditions caused by antibiotic-resistant E. coli.
• Naturally occurring phages are generally specific to a single species of bacteria. However, use of genetic engineering may allow drug companies to produce phages targeted to specific pathogenic bacteria while sparring the commensal (good) bacteria that contribute to human health (such as the bacteria found in the human intestines, vagina, and skin).

It is also important to consider environmental impacts of phage therapy. Researchers should avoid producing phages that could harm bacteria which contribute positively to the environment, agriculture, veterinary health, or human health.

Research use of any genetically modified microorganism should comply with biosafety guidelines issued by the National Institutes of Health and Centers for Disease Control. Review by an institutional biosafety committee (IBC) ensures the appropriate risk assessment has taken place and an adequate risk mitigation plan is implemented to protect researchers, the community, and the environment.

Bacteriophages aren’t necessarily the magic bullet to fix antibiotic resistance once and for all, but they certainly show promise in helping address the global problem. Research professionals interested in conducting research involving bacteriophages should first ensure their facilities have the appropriate biosafety protocols in place. It’s also important to be familiar with the risk profile associated with genetically modified bacteria and bacteriophages.

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