世界杯官方app scientists are advancing treatment against infectious diseases like tuberculosis

NOVEMBER 19, 2024 — 世界杯官方app faculty are leveraging their expertise to fight Mycobacterium tuberculosis (Mtb), the germ responsible for tuberculosis (TB) in humans, which primarily affects the lungs but can also infect other organs such as the brain, kidneys or spine.

According to The World Health Organization (WHO), approximately 11 million people fell ill to TB worldwide in 2023 and 1.25 million died. The WHO now estimates that TB, more than any other bacterial pathogen, is likely the world’s leading cause of death from a single infectious agent.

Mtb is known for its ability to resist drugs and evade the human immune system. Additionally, multidrug-resistant bacteria have emerged that are resistant to the two most potent TB drugs, isoniazid (INH) and rifampin. This is contributing to a growing need to better understand TB through fundamental research studies.

“Our research focus is on the discovery of new antimicrobial targets and innovative strategies for combating infectious diseases.”

Aimin Liu, Lutcher Brown Distinguished Chair in Biochemistry and professor in the 世界杯官方app Department of Chemistry, is the lead investigator on a novel research project funded by the National Institutes of Health’s (NIH) Research Project R01 grant, the fifth of its kind that Liu has been awarded as the principal investigator in the past nine years with the university. His team will receive $1.3 million in funding for the next four years on this anti-TB project in addition to his existing R01 project on natural product biosynthesis.

“Our research focus is on the discovery of new antimicrobial targets and innovative strategies for combating infectious diseases,” said Liu.

Liu is leading a team of researchers who are studying an enzyme called KatG (a short version of catalase-peroxidase), which is found in Mtb. KatG serves two functions. First, its peroxidase activity supports the pathogen’s growth, and this function is being used to activate INH to the actual active form that inhibits the synthesis of the Mtb cell membrane. The reduction due to KatG mutation resists INH medications commonly used to treat TB and is the most common cause of multi-drug resistance of TB. Secondly, its catalase activity rapidly converts hydrogen peroxide (H₂O₂) to molecular oxygen (O₂), which is essential for the pathogen to exist and survive inside an infected host.

Liu and his team of researchers hope that by gaining a thorough understanding of how the enzyme works, they can find strategies to reduce the catalase function while boosting the peroxidase activity to improve existing medications like INH.

While both catalytic functions of KatG are needed by the pathogen for different stages, they compete for H₂O₂ as their substrate. By inhibiting KatG’s catalase functions, Liu believes that existing drugs that are used to treat TB will become more efficient in combating those evolving Mtb strains with a reduced INH activation efficiency due to mutational reduction of the peroxidase activity.

“As a biochemist, I naturally came up with an idea. What if we inhibit KatG’s catalase activity?” said Liu. “KatG has been utilized as a pro-drug activator for more than 72 years. This is a utility enzyme, and it has never been considered as a drug target. Can it be both a target towards its catalase function to make the pathogen vulnerable to the peroxide killing inside a host and a utility with an increased peroxidase activity to activate INH?”

Liu and his team also landed on this innovative approach after studying how KatG performs at different temperatures, such as outside of the human body. Research has indicated that Mtb is capable of existing outside of the body for weeks. They found that KatG looked different in these types of environments and discovered a chemical group known as (N-OOH) located on KatG, which proved capable of blocking one of the functions that assists Mtb to survive in neutrophils and macrophages.

“This discovery underscores the critical role of temperature in biological systems, emphasizing the importance of studying both inside-host and outside-host conditions,” said Liu. “By considering the impact of temperature on microbial biology and chemistry, we can gain valuable insights into the factors contributing to the emergence of more virulent strains and develop more effective strategies to combat infectious diseases.”

Liu is collaborating with Jiasong Li, assistant professor of research in the 世界杯官方app Department of Chemistry and a leading author and key contributor to the project. They are joined by graduate students, Ran Duan, Ephrahime Traore, Romie Nguyen and Ian Davis ’21, who recently graduated from the Metalloprotein Lab and is currently the Chief of Operations in the Diagnostic Systems Division of the U.S. Army’s Medical Research Institute for Infectious Diseases.

Li and the graduate students completed the experimental work, analyzed data and participated in manuscript preparation. Additionally, Wendell Griffth, director of the 世界杯官方app Mass Spectrometry Core Facility, assisted with protein mass determinations.

“If this federally funded project goes well as planned, it will help the world develop new methods that will defeat emerging, multi-drug resistant MtB strains,” said Liu. “It will make INH, a common medication used against TB, continuously a more effective treatment that will save millions of lives each year.”

Liu leads the 世界杯官方app Metalloprotein Research Laboratory, which specializes in investigating how biomolecules use metals to perform chemistry necessary for life. His research career spans over 20 years and has been well-supported by the NIH, the National Science Foundation, the Welch Foundation and other funding agencies. His expertise includes biosynthesis, enzymology and protein biochemistry.

— Ryan Schoensee