Researchers publish new paradigm for attacking pathogens

Aggressive pathogens that infect humans can thrive in an oxygen-free environment via an ability to acquire the essential nutrient iron from heme (the cofactor that makes blood and muscle appear red).

Newly published research from the department of biochemistry and molecular biology reveals how a key enzyme at the center of this survival mechanism functions, a breakthrough that will help provide an opportunity for a new class of antimicrobial compounds:

While the pathways for degrading of heme by pathogens to acquire iron in the presence of oxygen, or aerobically, have long been understood, the research presents new insights into how pathogens living in an anaerobic environment utilize heme as an iron source to survive. The discovery infers broad implications for research on pathogenic enzymes and especially those that achieve antibiotic resistance.

"There are decades of published research analyzing heme degradation, but every single pathway that has been investigated ultimately required molecular oxygen as a co-substrate in the degradation of heme," said William Lanzilotta, associate professor in the department of biochemistry and molecular biology in the Franklin College of Arts and Sciences and a corresponding author on the paper. "Shigella, cholera, and the hemorrhagic E. coli strains all have specific genes that allow them to outcompete the healthy microorganisms living in the anaerobic environment of the human gut. Our fundamental question was: How are they able to degrade the heme and liberate the iron without molecular oxygen?"

Bacteria evolve various enzymatic pathways for survival in the body, and the researchers narrowed their focus to three genes in the hemorrhagic E. coli that had not been characterized. The discovery also builds upon recent developments in what is known as radical SAM chemistry, a designation for a superfamily of enzymes that are very old, from an evolutionary perspective.

This important new work flows out of a fundamental question about basic science that Lanzilotta and his research team, building on work from other researchers around the country, have answered with some intriguing and highly promising findings. The research infers great possibility in treating antibotic resistance, based on a new understanding of anaerobic conditions that harken back to early Earth and how life began. A wonderfully seductive, complex and illuminating story that spells out a path forward in fighting some of the worst human pathogens. Congratulations on this great work.

Image: Heme b molecule diagram, via wikimedia commons.