Multitarget TB drug could treat other diseases, evade resistance

April 17, 2014
University of Illinois chemists developed analogs of a new tuberculosis drug that could treat many other diseases and defy resistance. From left, research scientist Lici A. Schurig-Briccio, undergraduate Shannon Bogue, graduate student Xinxin Feng, research scientist Kai Li and chemistry professor Eric Oldfield. Credit: L. Brian Stauffer

A drug under clinical trials to treat tuberculosis could be the basis for a class of broad-spectrum drugs that act against various bacteria, fungal infections and parasites, yet evade resistance, according to a study by University of Illinois chemists and collaborators.

Led by U. of I. chemistry professor Eric Oldfield, the team determined the different ways the SQ109 attacks the , how the drug can be tweaked to target other pathogens from yeast to malaria – and how targeting multiple pathways reduces the probability of pathogens becoming resistant. SQ109 is made by Sequella Inc., a pharmaceutical company.

"Drug resistance is a major public health threat," Oldfield said. "We have to make new antibiotics, and we have to find ways to get around the resistance problem. And one way to do that is with multitarget drugs. Resistance in many cases arises because there's a specific mutation in the so the drug will no longer bind. Thus, one possible route to attacking the drug resistance problem will be to devise drugs that don't have just one target, but two or three targets."

Oldfield read published reports about SQ109 and realized that the drug would likely be multifunctional because it had chemical features similar to those found in other systems he had investigated. The original developers had identified one key action against – blocking a protein involved in building the cell wall of the bacterium – but conceded that the drug could have other actions within the cell as well since it was found to kill other bacteria and fungi that lacked the target protein. Oldfield believed he could identify those actions – and perhaps improve upon SQ109.

"I was reading Science magazine one day and saw this molecule, SQ109, and I thought, that looks a bit like molecules we've been studying that have multiple targets," Oldfield said. "Given its chemical structure, we thought that some of the enzymes that we study as cancer and antiparasitic drug targets also could be SQ109 targets. We hoped that we could make some analogs that would be more potent against tuberculosis, and maybe even against ."

By studying SQ109 for themselves, Oldfield's team determined that SQ109 does indeed block other proteins involved in critical functions in bacteria, fungi and parasites – but not humans. They found it inhibits two enzymes that make the molecule menaquinone, which is involved in generating the cell's energy. Then they found that SQ109 had a third action, called uncoupling, which makes the cell membrane permeable – essentially transforming the membrane from a wall to a screen door.

Then, the team created a dozen chemical analogs – molecules that are structurally and functionally similar, but tweaked to be more effective or less toxic – and tested them against cultures of bacteria, fungi, parasites and human cells. They found that they could make analogs with maximum effectiveness against certain classes of pathogens; for example, one analog turned out to be five times more potent against the tuberculosis bacterium than the original SQ109. They also found analogs that kill the parasites that cause the most serious and common form of malaria.

Now, the researchers are working with international collaborators to apply SQ109 analogs against other infectious diseases rampant in the tropical world, such as Chagas' disease, leishmaniasis and sleeping sickness.

Oldfield believes that multiple-target drugs, like SQ109 and its analogs, hold the key to antibiotic development in the age of and the rise of so-called "superbugs." Evidence supports that assessment: So far, in experiments with tuberculosis, no instances of SQ109 resistance have been reported.

Explore further: New compound overcomes drug-resistant Staph infection in mice

More information: The paper, "Multitarget Drug Discovery for Tuberculosis and Other Infectious Diseases," is available online: pubs.acs.org/doi/pdf/10.1021/jm500131s

Related Stories

New compound overcomes drug-resistant Staph infection in mice

January 7, 2013
Researchers have discovered a new compound that restores the health of mice infected with methicillin-resistant Staphylococcus aureus (MRSA), an otherwise dangerous bacterial infection. The new compound targets an enzyme ...

Promising class of antibiotics discovered for treatment of drug-resistant tuberculosis

March 5, 2014
St. Jude Children's Research Hospital scientists have discovered a promising new class of antibiotics that could aid efforts to overcome drug-resistance in tuberculosis (TB), a global killer. The drugs increased survival ...

Team develops way to make old antibiotic work against TB

January 27, 2014
St. Jude Children's Research Hospital scientists have discovered a promising new class of antibiotics that could aid efforts to overcome drug-resistance in tuberculosis (TB), a global killer. The drugs increased survival ...

Modified bone drug kills malaria parasite in mice

February 27, 2012
A chemically altered osteoporosis drug may be useful in fighting malaria, researchers report in a new study. Unlike similar compounds tested against other parasitic protozoa, the drug readily crosses into the red blood cells ...

Recommended for you

Research examines lung cell turnover as risk factor and target for treatment of influenza pneumonia

July 24, 2017
Influenza is a recurring global health threat that, according to the World Health Organization, is responsible for as many as 500,000 deaths every year, most due to influenza pneumonia, or viral pneumonia. Infection with ...

Scientists propose novel therapy to lessen risk of obesity-linked disease

July 24, 2017
With obesity related illnesses a global pandemic, researchers propose in the Journal of Clinical Investigation using a blood thinner to target molecular drivers of chronic metabolic inflammation in people eating high-fat ...

Raccoon roundworm—a hidden human parasite?

July 24, 2017
The raccoon that topples your trashcan and pillages your garden may leave more than just a mess. More likely than not, it also contaminates your yard with parasites—most notably, raccoon roundworms (Baylisascaris procyonis).

Google searches can be used to track dengue in underdeveloped countries

July 20, 2017
An analytical tool that combines Google search data with government-provided clinical data can quickly and accurately track dengue fever in less-developed countries, according to new research published in PLOS Computational ...

MRSA emerged years before methicillin was even discovered

July 19, 2017
Methicillin resistant Staphylococcus aureus (MRSA) emerged long before the introduction of the antibiotic methicillin into clinical practice, according to a study published in the open access journal Genome Biology. It was ...

New test distinguishes Zika from similar viral infections

July 18, 2017
A new test is the best-to-date in differentiating Zika virus infections from infections caused by similar viruses. The antibody-based assay, developed by researchers at UC Berkeley and Humabs BioMed, a private biotechnology ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.