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Targeting iron uptake to create a new class of antibiotics against UTIs

Targeting iron uptake to create a new class of antibiotics against UTIs

Last Reviewed : 01/05/2021
Targeting iron uptake to create a new class of antibiotics against UTIs

Press Release: 

  • At least half of all women will have a urinary tract infection during their lifetimes, and many of the infections -- which have increasingly become resistant to a wide array of antibiotics -- recur. Now, researchers report early progress toward developing a new class of antibiotics that would fight these infections by starving the causative bacteria of iron.

 

The researchers will present their results  at the American Chemical Society (ACS) Fall 2020 Virtual Meeting & Expo. We can't stop bacteria from evolving and developing resistance to antibiotics.The aim of the research is to develop a drug that acts in a different way from current drugs -- by depriving the bacteria of iron, a key nutrient essential to their survival.

Currently, most drugs that treat UTIs caused by uropathogenic E. coli (UPEC) either disrupt synthesis of the bacterial cell wall or interfere with bacterial DNA replication. Since the urinary tract is an iron-deficient environment, UPEC have evolved several ways to obtain iron, such as by producing molecules called siderophores that sop up iron bound to host proteins.

The researchers, who are at California Polytechnic State University, have collaborated on this project with other scientists at the University of Michigan School of Medicine. The collaborators previously showed that the iron acquisition process can be a target for small molecules for possible UTI treatment. In that study, they screened nearly 150,000 compounds and identified 16 that stop these bacteria from growing under iron-limiting conditions. Of these 16, two compounds were linked to disruption of the bacterial TonB system, which consists of three transmembrane proteins that help UPEC take up iron. Eagon's group is focusing on these two compounds for further study.

The team says that the goal is to prepare a library of inhibitors in which the hydroxyquinoline scaffold is modified with various functional groups. Plan is to screen them against UPEC and human cell lines to look for broad toxicity. After that, the compounds will be tested in animal models to see if they kill the bacteria in vivo. Once Eagon's team finishes preparing the complete hydroxyquinoline library, they plan to make variations of the second scaffold molecule.

Because they target iron uptake, this new class of drugs is expected to have no effect on beneficial E. coli strains in other regions of the body. Iron is plentiful in the body in non-urinary tract locations, so hindering iron uptake shouldn't cause a problem for these bacteria. Most current antibiotics, however, wipe out all strains, including beneficial gut flora. And because there is no TonB homolog found in humans, the possibility of toxic side effects would also be reduced compared to other antibiotics.

 

Story Source:

Materials provided by American Chemical Society.

American Chemical Society. "Targeting iron uptake to create a new class of antibiotics against UTIs." ScienceDaily. ScienceDaily, 17 August 2020. .

 Note: Original article may be edited for style and length.

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