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

August 17, 2020

WASHINGTON, Aug. 17, 2020 -- At 11 million cases annually, urinary tract infections (UTIs) are the most common outpatient infections in the U.S., according to the U.S. Department of Health and Human Services. At least half of all women will have a UTI 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 today at the American Chemical Society (ACS) Fall 2020 Virtual Meeting & Expo. ACS is holding the meeting through Thursday. It features more than 6,000 presentations on a wide range of science topics.

"You can't stop bacteria from evolving and developing resistance to antibiotics," says Mary Rose Ronquillo, an undergraduate student who works in the lab of Scott C. Eagon, Ph.D. "The aim of our 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.

"We selected one of these compounds as a scaffold to modify into potential small molecule inhibitors of the TonB system," M. Cole Detels, an undergraduate student in Eagon's lab, explains. The molecule is called 2-{[(3-chloro-4-methoxyphenyl)amino]methyl}quinolin-8-ol, or more simply, the "hydroxyquinoline scaffold."

After they made the scaffold molecule, Detels and Ronquillo prepared five variations, and another three are now in the purification stage. "While the synthesis of the potential drugs is relatively straightforward, purifying them from the soup of other chemicals used in their preparation has been challenging," Detels says.

The team says that the goal is to prepare a library of inhibitors in which the hydroxyquinoline scaffold is modified with various functional groups. "With this library in hand, we will work with our collaborators to screen them against UPEC and human cell lines to look for broad toxicity," Eagon says. "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.
-end-
A press conference on this topic will be held Wednesday, Aug. 19, at 1 p.m. Eastern time online at http://www.acs.org/fall2020pressconferences.

The researchers acknowledge support and funding from the Frost Fund and the National Science Foundation.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS' mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and its people. The Society is a global leader in providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a specialist in scientific information solutions (including SciFinder® and STN®), its CAS division powers global research, discovery and innovation. ACS' main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive press releases from the American Chemical Society, contact newsroom@acs.org.

Note to journalists: Please report that this research was presented at a meeting of the American Chemical Society.

Follow us: Twitter | Facebook

Title

Therapeutics targeting the iron acquisition systems of E. coli for the treatment of urinary tract infections

Abstract

Urinary tract infections (UTIs) are one of the most common bacterial infections in the United States, with approximately 11 million cases reported annually with an estimated treatment cost of $5 billion dollars per year. While UTIs occur in a variety of populations including children and the elderly, they are most prevalent in women. More than half of all women experience at least one UTI in their lifetime, and nearly one in three women will have received antibiotics to treat a UTI by the age of 24. UTIs are not only common, but also highly recurrent in women, children and the elderly. Nearly one-third of adult women with a reported UTI will experience recurrence within 4 months. These infections can cause a host of clinical manifestations, including cystitis (inflammation of the bladder), pyelonephritis (inflammation of the kidneys) and life-threatening urosepsis (septic poisoning from retained urinary substances).

The compounds in our presentation are thought to inhibit the iron uptake protein TonB, a protein that is not targeted by any current medication in clinical practice. Iron is essential for bacterial growth and virulence, but the urinary tract is an iron depleted environment. As a consequence, UPEC express multiple redundant iron acquisition systems which are highly upregulated during infection. A number of siderophores (iron chelating molecules) are produced by these systems which are able to extract iron bound to host proteins. The large number and variety of these iron acquisition systems and their upregulation underlines their importance for bacterial survival. While these iron acquisition systems use a variety of siderophores and outer membrane receptors, all of these systems require the TonB inner-membrane protein to transport the iron across the cytoplasmic membrane to the cell interior. Deletion of TonB from UPEC strains has been shown to greatly reduce virulence in a mouse model, demonstrating that TonB is an excellent target for a small molecule inhibitor. Targeting TonB also has the additional benefit of likely being active only in the urinary tract, preserving beneficial strains of E. coli in the gut where iron is more readily available. Additionally, there is no TonB homology in human cells, thus limiting potential toxicity.

American Chemical Society

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.