By: Helen Beilinson
A year and a half ago, I had temperatures over 100°F, could barely concentrate, and couldn’t sleep for more than two hours without waking up covered in sweat. After three days of somewhat tolerating this out of body experience, I realized that this wasn’t some kind of horrible cold and went to the student health care center. I had pyelonephritis, a bacterial infection of the kidney. I spent the next week in the hospital being pumped with antibiotics. Scarily, the antibiotics I was initially given did nothing to the invasive E. coli trying to take over my body. They were resistant to the drug that was supposed to kill them. It took two days of lab tests to realize this fact, after which I was immediately switched to another antibiotic, to which my new bacterial friends were not resistant. Thankfully, I was infection free and out of the hospital soon after.
I was fortunate in that a simple switch to another antimicrobial cleared my unwelcome squatters. In many cases, infectious bacteria are resistant to multiple drugs, termed multi-drug resistant organisms (MDRO), or, more comic book-ly, ‘super-bugs’. Bacteria evolve very quickly; modifying their genomes to select what works best for their environment or even obtaining bits of DNA from other bacteria that would aid them in survival. These bits of DNA encode genes that mutate at some of the fastest rates and that are one of the most frequently transferred from one bacterium to the next. They also encode genes that induce resistance to antimicrobials. The longer certain antimicrobials are used in the clinic, the more bacteria are able to acquire resistance genes, spreading resistance from bacterium to bacterium, from species to species. The need for new antimicrobials has been terrifyingly high for the last few decades because there has not been a new class of antibiotics discovered for the treatment of bacterial infection since 1987.
Many studies have been aimed at synthesizing new biomolecules in the lab in attempts to find a molecule never before encountered by bacteria that has antimicrobial potential. Other scientists have turned to a surprising place to find naturally occurring antimicrobials: bacteria.
Bacteria occupy what are called niches, a location that has a particular bacterium’s perfect temperature, humidity, and food. Although there are millions of niches that bacteria occupy, from lava pits to our pets’ guts, bacteria still have to compete with other bacteria for their niches. This is particularly true of locations that are not rich in nutrients—the bacteria not only have to fight for space, but also for food. To fight against invaders, bacteria use many strategies, including producing their own antimicrobials. One species of bacteria will produce molecules that harm other bacteria, while the producing species is unaffected by those molecules. These microbially-derived antimicrobial molecules have been the subjects of many scientific treasure hunts. Many niches have been explored, from the ground to the ocean (both of which have been very fruitful locations), but one recently published paper from the University of Tübingen looked for antimicrobials much closer… in their noses.
Any location on the human body that is exposed to the environment has a milieu of microbial life living in it. The nose is no exception. The nose, as well as the upper airway to which it is connected, is very nutrient poor, meaning that any bacteria that live there are in strong competition for space and food. Bacterial species from the human microbiota have been shown to produce bacteriocins, which are antimicrobial molecules. The authors of this study explored nasal commensals in attempts to identify antimicrobials capable of acting on Staphylococcus aureus, a bug that lives in the nose, respiratory tract, and on the skin. Although approximately 30% of the human population has S. aureus living in or on them, during times of immune suppression, S. aureus can cause skin and blood infections. Without antibiotic treatment, S. aureus bacteremia (bloodstream infection) has a fatality rate that ranges from 15 to 50 percent. Unfortunately, the prevalence of S. aureus in antimicrobial filled hospitals has lead the species to be highly resistant to many drugs. For example, MRSA is methicillin-resistant S. aureus, a highly difficult bacterium to treat. Many S. aureus strains are now classified as MDRO, as they are resistant to more drugs than just methicillin. Without novel antimicrobials to treat S. aureus infections, or any other MDRO infection, the fatality rates will only increase.
S. aureus is in the genus Staphylococcus and has many other genus family members, many of whom also live in the human nose. The authors of this study used a previously described collection of nasal Staphylococcus to screen the species’ ability to inhibit the growth of S. aureus. They identified one strain, called S. lugdunensis IVK28, which very strongly prevented the growth of S. aureus. In the hopes of identifying the specific molecule, or molecules, that S. lugdunensis uses as an antimicrobial against S. aureus, which could subsequently be used as clinical antimicrobials, the authors made a mutant library of S. lugdenensis. In essence, this means that they modified the entirety of the genome of S. lugdenensis randomly in many different ways. If a gene is mutated that is critical to repressing S. aureus growth, then that mutant would be unable prevent S. aureus growth. Then, they tested to see if any of the mutants were unable to repress S. aureus growth. When they found one mutant that did not have this antimicrobial property, they sequenced the bacteria’s genome to identify what gene was mutated. They found that the previously uncharacterized gene, which they named lugdunin, was mutated in this line of S. lugdunensis. This is the first clue showing that lugdunin could be a novel antimicrobial.
To test if lugdunin has antimicrobial properties outside of the context of S. lugdunensis, the authors isolated lugdunin on its own and found that it was able to independently act as an antimicrobial on S. aureus growth. This fact is important in that many molecules, particularly proteins, sometimes don’t function alone, working in conjunction with other proteins, or other biomolecules such as lipids or nucleic acids. An independently functioning molecule is much easier to work with, both in basic science characterization studies, as well as in the clinic. Lugdunin is a strong antimicrobial, with the ability to act against various strains of drug-resistant S. aureus and drug-resistant members of the Enterococcus genus, as well as many other bacteria. Importantly, lugdunin did not cause any damage to human cells (important when trying to develop a drug for human use). When the authors used a mouse skin infection model using S. aureus, lugdunin was able to eliminate most or all of the infection, a first critical experiment in demonstrating its potential as a clinically available antimicrobial.
The question of why some people are carriers of S. aureus, while others may go their entire lives without have one such bacterium ever live in or on them, has remained largely unanswered by scientists. To explore whether the presence of S. lugdunensis affects the presence of S. aureus, 187 patients’ nasal swabs were analyzed. A third of the patients had S. aureus, a number close to the national average, whereas a tenth of the patients had S. lugdunensis. The presence of S. lugdunensis, however, strongly decreased the likelihood that the patient had S. aureus. Although it couldn’t definitively be proved in humans, as human testing is strictly frowned upon by the higher powers that be in the scientific world, this finding was a critical step in understanding the relationship between the two Staphylococcus strains.
To further test this antagonized relationship, the authors asked whether lugdunin gave S. lugdunensis the capacity to outcompete S. aureus for nasal space. They found that this, in fact, is true. When they plated both bacteria on agar plates (basically thick jello with tons of nutrients), they found that S. lugdunensis always took over the plates within 72 hours. Even when the plate started as 90% aureus and 10% lugdunensis, three days later, there wasn’t a S. aureus bacterium to be found. When a mutated S. lugdunensis was used, a variant that lacked the lugdunin, S. aureus was able to take over the plate with ease. These findings show that S. lugdunensis is not just a member of many people’s nasal microbiota, but its ability to compete with S. aureus, thanks to its lugdunin molecule, can keep aureus at bay and prevent any potential infections it would cause.
The discovery of a potent antimicrobial that can act on drug-resistant bacteria is important. Of course, there is always the risk that bacteria will develop a resistance to this new antimicrobial, but when the authors of this study tested to see whether they can ‘force’ S. aureus to become lugdunin-resistant, they found that the rate of resistance development was minimal. Whereas S. aureus developed resistance to other drugs after even just a few days, lugdunin resistance wasn’t observed, even after a month. Lugdunin is an exciting new antimicrobial that hopefully will be able to treated MDRO-infected individuals soon. Additionally, as S. lugdunensis is a known safe nasal commensal, a fascinating potential of these findings is infection prevention, instead of treatment. Patients who are at a high risk for S. aureus infection can be colonized with S. lugdunenesis to make the bacteria work for us in exchange for the delicious mucus they feast on. The presence of this S. aureus fighter will lower the risk for S. aureus presence, even already drug-resistant S. aureus, in the nasal cavity, lowering the chance of a life threatening infection. Although it was a quiet field for a while, antimicrobial discovery has only been speeding up in the last few years. Exciting new discoveries are being published every few weeks and our ability to treat infections, as well as preventing them in the first place, is only getting better. Who knew that sharing boogers could save lives?