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A century ago, in the pre-antibiotic era, minor injuries and common infections could cause life-threatening illnesses. That’s why one of the greatest medical successes of the 20th century was the discovery of antibiotics. It saved countless lives and revolutionized modern medicine.
Nowadays, medical science is far more advanced than it was a century ago. Yet the emergence of antibacterial resistance to drugs now threatens the prevention and treatment of a growing range of infections, making antibiotic resistance one of the biggest threats to global health today, according to the World Health Organization.
Against this backdrop, Northern Illinois University faculty and student researchers are reporting important new strides toward the discovery of novel antibiotics that might someday save lives by warding off some hospital-associated superbugs.
“Over the past 25 years, there has been a dramatic decrease in the approval of new antibiotics by the U.S. Food and Drug administration,” NIU chemistry professor Timothy Hagen said. “That’s because most pharmaceutical companies discontinued their efforts to discover new antibiotics. Meanwhile, the need for antibiotics has grown dramatically due to resistance development.”
According to the Centers for Disease Control and Prevention (CDC), at least 2 million Americans become infected each year with superbugs—bacteria that are resistant to current antibiotics—and at least 23,000 people die each year from these infections.
In newly published research, Hagen and colleagues describe the synthesis and evaluation of a series of chemical compounds (known as pyrazolopyrimidines) that show promising antibiotic activity in a laboratory setting against certain kinds of Gram-negative bacteria, including Pseudomonas aeruginosa.
Gram-negative bacteria are increasingly resistant to most available antibiotics. P. aeruginosa is a pathogen linked to serious illnesses, particularly drug-resistant hospital-acquired infections among burn victims and ventilator-associated pneumonia. It is one of six types of bacteria that currently cause the majority of U.S. hospital infections, according to the CDC.
The NIU researchers are working to unravel the mysteries of metabolic pathways that are essential for the survival of disease-causing microorganisms. They tested compounds that inhibit the methylerythritol phosphate (MEP) pathway, used by several pathogenic bacteria to produce isoprenoids, which are diverse sets of compounds vital for all living things. By inhibiting the MEP pathway, bacteria are starved of nutrients and die.
Importantly, human bodies use a different pathway to produce these isoprenoids, so the compounds could potentially inhibit bacteria while reducing the risk of human side effects.
“The compounds that we synthesized will kill certain bacteria in a petri dish, and we believe they do this by inhibiting MEP metabolic pathways,” Hagen said. “I think it’s pretty significant.”
Hagen said the MEP pathway has seven enzymes, each of which could act as a “choke point” for shutting down the pathway. “This is one of the first reports of antibacterial compounds that bind to what’s known as the IspE enzyme,” Hagen said.
The findings are published in the December issue of Bioorganic & Medicinal Chemistry Letters. In addition to Hagen, authors from NIU include biology professor R. Meganathan and graduate students Gashaw M. Goshu (chemistry), Debarati Ghose (biology) and Joy M. Blain (chemistry).
The research also represents a collaborative effort between the NIU laboratories of Hagen and Meganathan and researchers from the Seattle Structural Genomics Center for Infectious Disease (SSGCID) located at the Center for Infectious Disease Research in Seattle, the drug-development company Beryllium near Seattle and the Center for Emerging and Reemerging Infectious Disease at the University of Washington.
“Due to the presence of an outer membrane in Gram-negative bacteria, they are naturally drug resistant,” said Goshu, an NIU Ph.D. student who was first author on the research paper.
“So, I am glad that the pyrazolopyrimidines can inhibit the growth of Burkholderia thailandensis and Pseudomonas aeruginosa,” he added. “I believe that these compounds can be used as a good starting point for the development of new antibacterial drugs.”
Most of the currently used antimicrobial agents were discovered from 1945 to 1960, during the golden era of antibiotics. Unfortunately, the discovery of new antimicrobial drugs has significantly declined since the early 1960s. The World Health Organization has warned that if appropriate measures are not taken, much of the past success in combating infectious diseases will be reversed.
“Although antibiotic resistance is a natural evolutionary process for bacteria adapting to their environment, it has been significantly accelerated by selective pressure employed by the overuse of antibiotics,” Hagen said.
The U.S. government, recognizing the need, is fast-tracking antibiotic research. New incentives and programs encourage the discovery and development of new antimicrobials with the ultimate goal to bring new antibiotics more rapidly to patients in need.
Collaborative efforts among the labs of Hagen, Meganathan and chemistry professor James Horn have placed NIU researchers at the forefront developing chemical compounds to fight infectious diseases. The research could be a foundation for future partnerships with small and large pharmaceutical companies, Hagen said, or it could lead to start-ups to help accelerate the research.
With continued success in the lab and collaborative public-private partnerships, development of new antibiotics, from petri dish to person, would likely require an additional three to five years, Hagen added.
The latest research was funded in part by the National Institute of Allergy and Infectious Diseases, which is one of the 27 institutes and centers of the National Institutes of Health.