The Enemy of My Enemy Is My Friend: Bacteriophages in a Post-Antibiotic Era
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In 2011, a 43-year-old recent lung transplantee arrived at New York City’s National Institutes of Health (NIH) hospital with a Klebsiella pneumoniae carbapenemase (KPC) infection. KPC isn’t just any ordinary bacteria—it’s a superbug: a bacteria highly resistant to most antibiotics. The NIH had never encountered this pathogen and took extreme precautions to contain KPC. These efforts were to no avail, and several patients contracted the bacteria, with 11 deaths from the infection over the next few months. Since then, KPC continues to live in the hospital and has made its way to other hospitals in at least 44 states.
KPC is just one of a growing number of superbugs. Our overuse of antibiotics has led to the evolution of numerous bacterial strains that are resistant to our antibiotics. Examples of antibiotic abuse by humans include taking antibiotics for nonbacterial infections, not completing antibiotic prescriptions so they make their way to landfill, and using nearly two-thirds of our medically important antibiotics in animal feed to mitigate the spread of disease. Given a population of bacteria, a small percentage might be resistant to the antibiotic due to a spontaneous mutation—however, the resistant bacteria multiply. Mechanisms for resistance include restricting antibiotic entry, digesting or deforming antibiotics, and mutating to no longer have or use components targeted by antibiotics. Gram-negative bacteria, like KPC, have an outer membrane that allows them to better prevent antibiotics from entering.
Counterproductively, as the use of antibiotics has ramped up, antibiotics research has dwindled. Most major pharmaceutical companies have abandoned the relatively unprofitable field. As a result, we are entering an era in which previously commonplace bacterial infections could be lethal. In fact, someone in the US dies from an antibiotic-resistant infection every 15 minutes. Fortunately, a new method of treating bacterial infections is being looked into: phages.
Bacteriophages, or phages, are viruses that parasitize bacteria. They generally have an icosahedron protein capsule containing their genetic material and numerous filaments protruding from their tail. To attack a bacteria, they inject their genetic material into the bacteria, hijacking the bacteria to produce copies of the phage. For virulent phages, these new phages quickly lyse the bacteria and are released into the environment. Temperate phages, on the other hand, remain in the host bacteria and multiply as the bacteria reproduces, lysing the bacteria after a trigger. Once phages are free, they begin attacking surrounding bacteria.
Using the phages as treatment proved helpful for one patient. One woman, who experienced a broken femur, contracted KPC after doctors operated on her thighbone. For two years, the patient remained infected with KPC as dose after dose of antibiotic treatment failed to eradicate the bacteria. Her medical team then looked into phage therapy as a solution, and cleared her infection after 15 rounds of phage therapy that combined the use of phages and antibiotics over the course of three months.
The sheer quantity of phages already makes it a more promising avenue for bacterial infection treatment than antibiotics. There are ten times as many phages as there are bacteria on the planet. The population of phages (and bacteria) is also orders of magnitude higher than the number of available antibiotics, which means that the likelihood of there being a phage capable of attacking a particular bacteria is greater.
Phages also have the capacity to change in response to bacteria gaining resistance. Bacterial resistance to phages occurs by cleaving the phage’s genetic material using restriction enzymes, remembering parts of phage genetic sequences, or initiating cell death upon phage entry. In response, phages have evolved to bypass these bacterial defense mechanisms. For example, a phage may trick a bacterium into extending methylation to phage genetic material, thus preventing its degradation by restriction enzymes. Phages may also lose the sequences of their genetic material that have been memorized by bacteria using CRISPR. Phages are able to make these adaptations quickly due to their high genetic variability.
Luckily, human cells are not victims of phages’ ruthless parasitism and incessant evolution. This is because human cells are eukaryotic while bacterial cells are prokaryotic and have structures that allow phages to replicate. Phages are unable to penetrate eukaryotic cells but can penetrate Gram-negative bacteria membranes effectively.
Though there are other clinical examples of phage therapy use, the field is still budding and significant public skepticism of the treatment remains, largely due to the way that antibiotics have previously dominated antimicrobial development. Some people fear that bacteriophages may not be as benign to eukaryotic cells as we may have previously thought.
Nonetheless, phages have roamed this planet for ages before us, and their harsh methods of attacking bacteria might just revitalize our antimicrobial toolbox. Though they aren’t considered organisms, these tiny molecules might be our best tool in mitigating the impending superbugs crisis. As more research is conducted on phage therapy, it will hopefully become a treatment used in conjunction with or sometimes even in place of antibiotic medication.