Researchers Find Genes Essential to Growth of Drug-Resistant Bacteria

Their study reveals multiple new drug targets for this infection and suggests that typical methods of studying bacteria in rich laboratory media may not be the best way to identify antimicrobial drug targets.

Their findings, which may have implications for other Gram-negative bacteria, were published as an “editor’s choice” paper in mBio.

During the study, researchers tried to better understand what A. baumannii—a bacteria responsible for a rising number of hospital-acquired infections—needs in order to grow when infecting people.

Typically, scientists find the essential genes for microbial pathogens by growing the bacteria under optimal conditions, explains study co-author Thomas A. Russo, MD, professor of medicine and microbiology and immunology.

However, laboratory conditions create a different type of environment than the human body, where certain nutrients the bacteria need are present in very low amounts, and where the bacteria encounter immune and inflammatory responses.

“We were purposely trying to test for genes that are important for growth in these more realistic environments,” explains lead author Timothy C. Umland, PhD, professor of structural biology and a research scientist at Hauptman-Woodward Medical Research Institute.

The team performed genetic screening to identify bacterial genes required for the growth and survival of A. baumannii in human ascites, a peritoneal fluid present under a variety of pathologic conditions.

“We found that nearly all of these 18 genes had not been identified as essential in the Database of Essential Genes”—the record of genes considered indispensable to support cellular life—“because they weren't necessary for growth in an ideal laboratory environment,” Russo says.

“This is a large set of genes that has been flying under the radar.”

A. baumannii doesn’t generally infect healthy people, but it can be fatal to patients with serious illnesses, those who have had surgeries and the elderly. Soldiers returning from Iraq and Afghanistan with battlefield injuries also risk infection.

“What's challenging about A. baumannii is that it can survive in the hospital environment and is very hard to eradicate with common disinfectants, leading to health care-associated infections,” Umland says.

Many strains are resistant to nearly all anti-microbial drugs and some strains are resistant to all of them, Russo notes. Currently, there are no new agents being tested for human use that are active against the bacteria, he adds.

The newly identified genes suggest new, high-value drug targets for A. baumannii infections and may be relevant to other Gram-negative infections.

“So far, our computational models show that these genes seem to be conserved across Gram-negative infections, meaning they may lead to new drugs that would be effective for other drug-resistant infections as well,” Umland explains.

The researchers are now pursuing antibacterial drug discovery efforts focused on the newly identified bacterial targets.

The research was funded by grants from the Telemedicine and Advance Technical Research Center of the U.S. Army Medical Research and Materiel Command, an interdisciplinary grant from UB and a VA Merit Review grant from the U.S. Department of Veterans Affairs.

Other co-authors on the paper are L. Wayne Schultz, PhD, of the Department of Structural Biology, and Ulrike MacDonald, Janet M. Beanan and Ruth Olson of the Departments of Medicine, Microbiology and Immunology, and UB’s Witebsky Center for Microbial Pathogenesis.