Ingenious: Breaching Molecular Walls

Chemistry Professor Paul Hergenrother’s work focuses on antimicrobial- resistant pathogens. (Image by Fred Zwicky)

Researchers have long run up against “a wall” in attempting to thwart some of the world’s deadliest bacteria. That’s because antibiotics cannot penetrate the membrane walls of those pathogens, says Paul Hergenrother, U of I chemistry professor. But his lab has found the key to slipping past bacterial defenses.

Hergenrother and his team, led by former graduate student, Emily Geddes, PHD ’22 LAS, discovered the “entry rules” that allow antibiotics to get through the outer membrane of Pseudomonas aeruginosa, a dangerous bacterium responsible for tens of thousands of hospital infections every year.

Pseudomonas is hard to treat, but by determining the qualities that allow drugs to break through the bacterium’s outer membrane, Hergenrother’s team may have opened the door to a world of new treatments to fight this dangerous enemy.

There are six major known antimicrobial-resistant pathogens. Each is represented by a letter in the acronym ESKAPE, with the “P” standing for Pseudomona. They are all especially difficult to treat, and four of the six deadly bacteria are classified as “gram-negative,” which means they have an extra outer membrane.

“It’s very challenging for drugs to get through that outer membrane and into the cell to hit targets that kill the bacteria,” Hergenrother says. “The gram-negative challenge and the failures of standard approaches have been well documented.”

His lab, however, has already successfully met that challenge. In 2017, Hergenrother’s team targeted another gram-negative bacterium—Escherichida coli (E. coli). They found the entry rules that allow certain drugs to get into the “porin proteins” that channel molecules through E. coli’s double membrane.

The entry rules for E. coli worked with three of the four gram-negative bacteria in the ESKAPE acronym—but not for Pseudomonas. To figure out how to get through the Pseudomonas barrier, Hergenrother’s team screened hundreds of compounds. They then used machine learning to pinpoint a rare combination of chemical traits common among those that could break through the membrane barrier.

Next, they synthesized a version of the antibiotic fusidic acid, folding in the chemical traits they had identified. Under normal conditions, fusidic acid would have no possible way to break through Pseudomonas’ double membrane. But by endowing it with the traits Hergenrother’s team discovered, it breached the bacterium’s wall.

The FDA has not approved a new class of antibiotic drugs to treat gram-negative pathogens in more than 50 years. But Hergenrother believes that could change. “Our understanding of accumulation rules for these four key gram-negative pathogens is deepening, and this information is actionable in the development of new antibiotics,” he says.