A Growing Health Crisis

Photograph by Adam Voorhes

While studying influenza in 1928, a British scientist noticed that mold had developed on a petri dish in which staphylococci was growing. That scientist was Alexander Fleming, and he had just discovered penicillin, the world’s first antibiotic. One of the greatest advances in medicine, these so-called wonder drugs would save millions of lives over the next century and radically improve the way we treat bacterial infections.

Yet today, an antibiotics crisis looms. A growing number of people are dying from infections and strains of pneumonia, tuberculosis, and other diseases that have become impervious to antibiotics, due partially to the drugs’ overuse. Without action, many modern medicines soon could be rendered completely ineffective.

Scientists at The University of Texas at Arlington are addressing the escalating public health issue. Researchers from a variety of fields are harnessing the body’s natural defenses to fight bacteria, studying enzymes to facilitate the development of new drugs, and seeking new and improved ways to treat infections in hospitals and military facilities.

Their research, which has drawn millions of dollars in grants, is urgent. The Centers for Disease Control and Prevention (CDC) warns that antibiotic resistance is one of the most pressing challenges of our time—each year in the United States at least 2 million people fall ill from antibiotic-resistant infections, and some 23,000 people die from them. Further, such infections are associated with close to $20 billion in direct medical costs annually, according to the Alliance for the Prudent Use of Antibiotics.

The crisis extends far beyond the United States. In India, for example, more than 58,000 babies died in one year as a result of infections with resistant bacteria, typically passed on from their mothers.

At UTA, bacteria research got a recent boost with the 2018 opening of the Science & Engineering Innovation & Research building. The $125 million, state-of-the-art facility is helping to push the University forward as a leading health science research and teaching institution. Employing the modern concept of research lab neighborhoods, the facility drives collaboration and creativity across a multitude of disciplines, including science, engineering, nursing, kinesiology, and public health.

“Our research programs on antibiotic resistance are evidence of UTA’s growing expertise in the health science field, as well as the University’s commitment to lead on a national scope,” College of Science Dean Morteza Khaledi says. “Research being done in laboratories here could lead to life-saving breakthroughs that benefit all of us.”

A biological boost

Mark Pellegrino has a question.

“What if we could stimulate the body’s own defenses to fight and protect against pathogens like bacteria?”

This query lies at the heart of a $1.8 million grant the biology assistant professor received from the National Institutes of Health. Leading a team of UTA researchers, Dr. Pellegrino—who joined the University in 2016 from Memorial Sloan Kettering Cancer Center in New York—is looking at how mitochondria defend themselves in an effort to develop new ways to boost immunity and improve resistance to bacteria.

Assistant Professor Mark Pellegrino

Mitochondria play a critical role in cells. They are responsible for turning the sugar, fat, and protein we eat into forms of energy the body needs to survive. They also help to regulate cell death, a necessary process to prevent the spread of infection or growth of a tumor.

When mitochondria are stressed by diseases, toxins, or infections, a protein enters the cell nucleus and binds to certain DNA sequences to unlock genes to repair the mitochondria. That signaling pathway is called the mitochondria unfolded protein response.

In previous research, Pellegrino identified a protein, known as ATFS-1, that regulates the signaling pathway in C. elegans, a primitive worm about 1 millimeter long that shares numerous characteristics with humans. Both the protein and signaling mechanism are instrumental in helping mitochondria defend against pathogens, he found.

“Because of their critical roles in the cell, mitochondria are clear targets of pathogens,” explains Pellegrino, whose initial discovery that mitochondria are important to innate immunity was published in Nature in 2014.

Using the same small worm, he is now studying how those pathogens interact with mitochondria’s defense and repair system. These discoveries could lead to new treatments for bacterial infections and some cancers.

“Antibiotic resistance is growing, and the number of new antibiotics being developed is extremely limited,” Pellegrino says. “We know that we must develop new treatment methods. An alternative is not to simply treat the bacteria, but to boost our own immune systems and improve our body’s resistance.”

A roadmap for enzymes

Thousands of enzymes are at work in the human body, speeding up the chemical reactions necessary for everyday functions, such as digestion, blood clotting, and toxin removal.

The human body depends on these enzymes for survival, yet the way many of them function remains a mystery. To that end, a biochemist at UTA is studying a set of enzymes in hopes of creating new drugs to fight bacterial infection, cancer, and even neurodegenerative diseases.

Associate Professor Brad Pierce

“If I understand how a car runs, I can fix it,” says Brad Pierce, associate professor of biochemistry. “In many respects, the human body is similar. Enzymatic pathways can be considered as interconnecting components of a complex machine. Without knowledge of how these components interact, it is nearly impossible to repair. But if we understand how these enzymes function collectively, we can begin to rationalize how to develop effective strategies to treat diseases associated with enzymatic dysfunction.”

Dr. Pierce, who recently received nearly $430,000 from the National Institutes of Health to continue his work, is mapping the function of enzymes related to the metabolism of sulfur, which is one of the most abundant elements in the body.

“If I understand how a car runs, I can fix it. In many respects, the human body is similar.”

“Despite its physiological importance, there is still a great deal we don’t know about how sulfur is metabolized in the human body,” Pierce says. “Our research seeks to change that.”

Enzymes involved in the sulfur-oxidation process are gaining attention as potential drug targets for the development of antibiotics and therapies for cancer and inflammatory disease, in large part because patients with autism, Down syndrome, and Alzheimer’s demonstrate abnormal sulfur metabolism.

To study the processes, Pierce is mapping three key enzymes—cysteine dioxygenase, cysteamine dioxygenase, and 3-mercaptopropionic acid dioxygenase. He and his team use a rapid-mix, freeze-quench technique to monitor the progress of chemical reactions at millisecond intervals. Ultimately, Pierce wants to create a step-by-step picture of how these enzymes function in both mammals and bacteria.

Specifically, he wants to better understand how the behavior of the enzymes changes in the presence of pathogens like bacteria.

“As with most things, the devil is in the details,” Pierce says. “Only by mapping out how human and bacterial enzymes deviate can we identify tailored therapies for specific pathogens. These will be less likely to elicit adverse side effects on our own physiology. In short, by understanding the function of these enzymes, we can rationalize the synthesis of entirely new therapeutic agents.”

A transformation for treatment

Each year in the U.S., thousands of patients pick up bacterial infections while receiving care in hospitals. According to the CDC, on any given day about one in 31 hospital patients has a health care-associated infection, increasing the risk of it spreading to others and, in turn, prolonging their hospital stays.

With antibiotics quickly becoming less effective, new treatments are needed to battle infectious diseases in hospitals and military facilities. That’s why Associate Professor He Dong is developing a method to treat and heal antibiotic-resistant infections not with drugs, but with a synthetic nanomaterial.

“We desperately need new ways to fight the growing number of antibiotic-resistant infections,” Dr. Dong says. “Synthetic antimicrobial nanomaterials have the potential to transform the health care industry and the use of conventional antibiotics.”

Scientists first discovered antimicrobial nanomaterials about 30 years ago, but their use stalled because they are toxic toward healthy human cells.

Associate Professor He Dong

Using a new technique, Dong and her team are developing materials that only target toxic bacteria and are biocompatible with healthy mammalian cells. Called synthetic self-assembling antimicrobial nanofibers (SAANs), the peptides self-assemble into a larger nanofiber shape that can punch holes in the bacteria membrane, killing the pathogen. Compared to traditional antibiotics, they may be less prone to developing antibiotic resistance because genetic modification of the cell membrane, which they target, is more difficult. The molecules also have the potential to treat infections on external surfaces and internally through oral or intravenous treatments.

Dong was awarded a prestigious National Science Foundation Faculty Early Career Development (CAREER) grant worth nearly $500,000 for her work. As part of the project, she is hoping to further understand how SAANs are so effective against bacteria without harming healthy cells.

Her collaborators include faculty from UTA’s Department of Bioengineering and clinicians in the Division of Infectious Diseases and Geographic Medicine at UT Southwestern Medical Center. Once they have developed the materials, the team will test the antimicrobial activity in different animal models to evaluate its effectiveness.

“Today’s antibiotics crisis requires us to think outside of the box for the next generation of treatment,” Dong says. “We are confident these antimicrobial nanomaterials can lead to real, life-saving applications in hospitals and military facilities. i

Bacteria images by Biomedical Imaging Unit, Southampton General Hospital/Science Photo Library