Want to Beat Antibiotic-Resistant Superbugs? Rethink That Strep Throat Remedy

Got a sore throat? The doctor may write a quick prescription for penicillin or amoxicillin, and with the stroke of a pen help diminish public health and your own future health by helping bacteria evolve resistance to antibiotics.

It’s time to develop alternatives to antibiotics for small infections, according to a new thought paper by scientists at the Georgia Institute of Technology, and to do so quickly. It has been widely reported that bacteria will evolve to render antibiotics mostly ineffective by mid-century, and current strategies to make up for the projected shortfalls haven’t worked.

One possible problem is that drug development strategies have focused on replacing antibiotics in extreme infections, such as sepsis, where every minute without an effective drug increases the risk of death. But the evolutionary process that brings forth antibiotic resistance doesn’t happen nearly as often in those big infections as it does in the multitude of small ones like sinusitis, tonsillitis, bronchitis, and bladder infections, the Georgia Tech researchers said.

“Antibiotic prescriptions against those smaller ailments account for about 90 percent of antibiotic use, and so are likely to be the major driver of resistance evolution,” said Sam Brown, an associate professor in Georgia Tech’s School of Biological Sciences. Bacteria that survive these many small battles against antibiotics grow in strength and numbers to become formidable armies in big infections, like those that strike after surgery.

“It might make more sense to give antibiotics less often and preserve their effectiveness for when they’re really needed. And develop alternate treatments for the small infections,” Brown said.

Brown, who specializes in the evolution of microbes and in bacterial virulence, and first author Kristofer Wollein Waldetoft, a medical doctor and postdoctoral research assistant in Brown’s lab, published an essay detailing their suggestion for refocusing the development of bacteria-fighting drugs on December 28, 2017, in the journal PLOS Biology.

Duplicitous antibiotics

The evolution of antibiotic resistance can be downright two-faced.

“If you or your kid go to the doctor with an upper respiratory infection, you often get amoxicillin, which is a relatively broad-spectrum antibiotic,” Brown said. “So, it kills not only strep but also a lot of other bacteria, including in places like the digestive tract, and that has quite broad impacts.”

E. coli is widespread in the human gut, and some strains secrete enzymes that thwart antibiotics, while other strains don’t. A broad-spectrum antibiotic can kill off more of the vulnerable, less dangerous bacteria, leaving the more dangerous and robust bacteria to propagate.

“You take an antibiotic to go after that thing in your throat, and you end up with gut bacteria that are super-resistant,” Brown said. “Then later, if you have to have surgery, you have a problem. Or you give that resistant E. coli to an elderly relative.”

Much too often, superbugs have made their way into hospitals in someone’s intestines, where they had evolved high resistance through years of occasional treatment with antibiotics for small infections. Then those bacteria have infected patients with weak immune systems.

Furious infections have ensued, essentially invulnerable to antibiotics, followed by sepsis and death.

Alternatives get an “F”

Drug developers facing dwindling antibiotic effectiveness against evolved bacteria have looked for multiple alternate treatments. The focus has often been to find some new class of drug that works as well as or better than antibiotics, but so far, nothing has, Brown said.

Wollein Waldetoft came across a research paper in the medical journal Lancet Infectious Diseases that examined study after study on such alternate treatments against big, deadly infections.

“It was a kind of scorecard, and it was almost uniformly negative,” Brown said. “These alternate therapies, such as phage or anti-virulence drugs or, bacteriocins — you name it — just didn’t rise to the same bar of efficacy that existing antibiotics did.”

“It was a type of doom and gloom paper that said once the antibiotics are gone, we’re in trouble,” Brown said. “Drug companies still are investing in alternate drug research, because it has gotten very, very hard to develop new effective antibiotics. We don’t have a lot of other options.”

But the focus on new treatments for extreme infections has bothered the researchers because the main arena where the vast portion of resistance evolution occurs is in small infections. “We felt like there was a disconnect going on here,” Brown said.

Don’t kill strep, beat it

The researchers proposed a different approach: “Take the easier tasks, like sore throats, off of antibiotics and reserve antibiotics for these really serious conditions.”

Developing non-antibiotic therapies for strep throat, bladder infections, and bronchitis could prove easier, thus encouraging pharmaceutical investment and research.

For example, one particular kind of strep bacteria, group A streptococci, is responsible for the vast majority of bacterial upper respiratory infections. People often carry it without it breaking out.

Strep bacteria secrete compounds that promote inflammation and bacterial spread. If an anti-virulence drug could fight the secretions, the drug could knock back the strep into being present but not sickening.

Brown cautioned that strep infection can lead to rheumatic heart disease, a deadly condition that is very rare in the industrialized world, but it still takes a toll in other parts of the world. “A less powerful drug can be good enough if you don’t have serious strep throat issues in your medical history,” he said.

Sometimes, all it takes is some push-back against virulent bacteria until the body’s immune system can take care of it. Developing a spray-on treatment with bacteriophages, viruses that attack bacteria, might possibly do the trick.

If doctors had enough alternatives to antibiotics for the multitude of small infections they treat, they could help preserve antibiotic effectiveness longer for the far less common but much more deadly infections, for which they’re most needed.

Deadly Bacteria Share Weapons to Outsmart Antibiotics

Bacteria are rapidly developing resistance mechanisms to combat even the most effective antibiotics. Each year in the United States over 23,000 people die as a result of bacterial infections that have no treatment options, according to the Centers for Disease Control. Infections with antibiotic-resistance bacteria are extremely difficult to treat, requiring costly or toxic medications that do not always work. Scientists are constantly working to understand the mechanisms bacteria use to outsmart antibiotics and develop resistance. These mechanisms include metallo-β-lactamases (MBLs), enzymes produced by bacteria that can bind to and inactivate antibiotics. Enzymes like MBLs are one way bacteria are defying all available tools and becoming antibiotic resistant.

A team of researchers at Case Western Reserve University (CWRU), Massachusetts Institute of Technology, and Universidad Nacional de Rosario and the National Research Council (CONICET) from Argentina have identified a bacterial mechanism that stabilizes certain MBLs in cell membranes and enables their spread into the environment. This mechanism clarifies one way certain bacteria are outsmarting the immune system and becoming extremely antibiotic-resistant. The work was led in part by Robert Bonomo, MD, professor of medicine, pharmacology, molecular biology, and microbiology at Case Western Reserve University School of Medicine and chief of medical service at the Louis Stokes Cleveland Veterans Affairs Medical Center.

“One of the most serious problems facing medicine today is the emergence of multi-drug resistant bacteria,” according to Bonomo. “MBLs are the most concerning as they make bacteria resistant to the ‘last resort’ antibiotics, carbapenems.” Carbapenems are used to combat infections for which there are no other antibiotic options.

Clinically relevant MBLs are found between layers of bacterial cell membranes. In contrast to other types of carbapenemases, MBL enzymes rely on zinc ions to properly function. The immune system produces proteins that hide zinc ions and starve bacteria of zinc in an effort to combat infection. The researchers discovered that most MBLs produced by bacteria during zinc-limited conditions are unstable and are rapidly degraded by the bacteria.

One recently identified form of MBL, called New Delhi metallo-β-lactamase (NDM-1) can retain its function even without zinc. Bonomo and colleagues showed that NDM-1 resists destruction triggered by low zinc by anchoring itself in bacterial membranes. A fatty tail at one end of the NDM-1 protein sticks into the outer membrane of potentially harmful bacteria such as Escherichia coli and Pseudomonas aeruginosa. This tail has a protective effect and is thought to help NDM-1 avoid destructive enzymes between bacterial membranes. Similar mechanisms have been observed in other bacterial species, but have not previously been linked to an evolutionary advantage to escape the action of antibiotics.

The research team also observed that bacteria with NDM-1 in their membranes are also able to shed “outer-membrane vesicles” containing the enzyme. These membrane-bound sacs bud off from bacteria. As the vesicles disperse into the bacterial microenvironment, NDM-1 enzymes in them can protect neighboring bacteria that might be otherwise susceptible to antibiotics. Outer-membrane vesicles may also be a vehicle by which the NDM-1 gene and enzyme can spread between bacteria.

Bacteria producing NDM-1 are highly antibiotic resistant and represent a major public health concern as they cause infections for which there is no cure. The gene encoding NDM-1 is quickly spreading across bacterial species and has been found in water samples from India, Bangladesh, and China in a region encompassing almost 40% of the world population.

According to Alejandro Vila, PhD, director of the Instituto de Biología Molecular y Celular at Universidad Nacional de Rosario and co-senior author on the published research, “this dissemination has been favored by membrane anchoring of the protein. This finding reveals a potential Achilles’ heel; interfering with membrane anchoring could thwart the worldwide dissemination of superbugs.”

Together, the studies by Bonomo, Vila, and colleagues provide clarity on the bacterial mechanism behind one of the most prevalent bacterial carbapenemase identified to date, NDM-1. Understanding the mechanism “allows us to begin considering novel agents that can target this process,” according to. Bonomo. New potential targets for antibacterial drug development could include the lipid tail of NDM-1 or outer membrane vesicles.