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Boll receives $390,000 NIH grant to study multidrug resistance in bacterial pathogens

From left, Misha Kazi, Joseph Boll, Feroz Ahmed, and Katie Kang
From left, Misha Kazi, Joseph Boll, Feroz Ahmed, and Katie Kang

A biology researcher at The University of Texas at Arlington is studying ways that bacteria become resistant to antibiotics in order to improve treatment strategies for patients.

Joseph Boll, assistant professor of biology, received a two-year, $390,000 exploratory grant from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases for the study. The project is titled “Solving a Multidrug Resistance Puzzle: Complete Loss of Lipooligosaccharide,” and its goal is to identify and understand how a pathogen develops resistance to antibiotics.

Feroz Ahmed, Katie Kang, and Misha Kazi, all graduate students in Boll’s lab, are working with him on the project.

Most bacteria are classified into two groups — Gram-positive or Gram-negative — based on unique components within the cell envelope. Gram-negative bacteria include some of the most difficult to treat pathogens. The emergence of hospital-acquired multidrug-resistant Gram-negative bacteria is a growing problem worldwide and a serious public health threat.

“Many bacterial pathogens can develop resistance to antimicrobials. In Gram-negative bacteria, resistance is often associated with modification of the cell-surface outer membrane,” Boll said. “The aim of this proposal is to characterize a novel drug resistance mechanism to provide the basic science framework for future antimicrobial treatment options.”

Acinetobacter baumannii, or A. baumannii, is a Gram-negative bacteria which is found almost exclusively in hospital and clinical settings. A. baumannii has become increasingly problematic since the start of the Iraq War in 2003. It emerged in treatment facilities during the war and soon spread to civilian hospitals. It has become widespread over the past decade because it is resistant to desiccation, biocides and multiple antibiotic medications. One highly effective antimicrobial medication, called colistin, targets the Gram-negative cell surface molecule, lipooligosaccharide, to kill the bacterium.

Colistin, which has been around for decades, today is often used as a drug of last resort because of its toxic effects on the kidneys. While colistin resistance was once rare, A. baumannii has developed a unique resistance mechanism.

A. baumannii can completely shut down lipooligosaccharide biosynthesis to develop multidrug resistance to many prescribed antibiotics, including colistin,” Boll said. “This finding is surprising because lipooligosaccharide was thought to be required for Gram-negative viability, but this mechanism proves otherwise.

Since A. baumannii is an emerging pathogen and thrives in environments detrimental to most other bacterial pathogens, understanding the mechanisms that mediate antimicrobial resistance, biocide tolerance and desiccation will inform future treatment strategies.”

Boll will seek to determine the molecular factors contributing to antimicrobial resistance, which will increase understanding of how Gram-negative bacteria assemble their cell envelope and support development of alternative therapeutics, he said.

“First, we will characterize the cell-surface outer membrane proteins that support lipooligosaccharide-A. baumannii survival,” he said. “Then we will characterize the BaeSR two-component system, which is a signal transduction pathway that likely regulates many of the resistance mechanisms.”

A signal transduction pathway is a set of chemical reactions in a cell that occurs when a molecule attaches to a receptor on the cell membrane and elicits a response.

“Completion of these aims will advance our body of knowledge to understand the essentiality of lipid A in Gram-negative bacteria and provide understanding of a molecular mechanism required for a novel multidrug resistance mechanism,” Boll said. “Furthermore, the findings from this project could potentially lead to development of novel therapeutics and improved vaccines.”

Clay Clark, professor and chair of the UTA Department of Biology, said Boll’s project holds promise for advancement in the ongoing fight against multidrug-resistant bacteria, which threatens the health of millions annually.

“Drug-resistant pathogens are an increasingly serious problem in medicine and the treatment of infections,” Clark said. “Anything that could help scientists create alternative methods of treatment would be a real breakthrough, and Dr. Boll’s research has that kind of potential.”

Boll received a B.S. in Microbiology from Texas Tech University in 2007 and a Ph.D. in Molecular Microbiology from UT Southwestern Medical Center at Dallas in 2013. He completed a postdoctoral fellowship at UT Austin and the University of Georgia before joining UTA in 2017.