NOV 17, 2015 11:21 AM PST

Scripps Florida Scientists Discover New Compounds with Potential to Treat Persistent Tuberculosis

Tuberculosis has been infecting humans for several millennia, making it one of the most horribly successful diseases in history. Today, it is still a major killer, responsible for some 1.5 million deaths each year.

In a substantial number of cases—some two billion, in fact—the tuberculosis bacteria (Mycobacterium tuberculosis) isn’t active at all. Instead, it hides inside cell aggregates, latent and persistent, waiting to break out.

Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered several first-in-class compounds that target these hidden infections by attacking a critical process the bacteria use to survive in the hostile environment of the lungs.

The study, which was published recently online ahead of print by the journal ACS Chemical Biology, was led by Kate Carroll, a TSRI associate professor.

“With the help of Scripps Florida’s high-throughput screening facility, we looked at nearly 40,000 compounds before we uncovered these new, potent inhibitors that attack an enzyme critical to the survival of persistent tuberculosis,” Carroll said. “Thanks to our collaborators in India with access to drug-resistant patient isolates, we were able to demonstrate that these compounds also show excellent activity against multidrug resistant (MDR) and extensively drug-resistant (XDR) strains, in addition to the standard laboratory reference strain, H37Rv, of M. tuberculosis.”
Mycobacterium Tuberculosis

In 2013, the World Health Organization reported that nearly a quarter of all new and previously treated cases of the disease were multidrug resistant—difficult to diagnose and even more difficult to treat.
James Collins, who is the Termeer Professor at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard University, praised the new study, saying, “This is a marvelous work and an important contribution to the field.”

A Promising New Target

The study identified at least three different structural classes of compounds known as APSR inhibitors active against the bacteria, particularly those multidrug-resistant and extensively drug-resistant strains. The APSR enzyme is essential to the production of reduced sulfur compounds needed to stabilize the cellular environment—and the target of Carroll’s new inhibitors, which aim to kill persistent tuberculosis by disrupting this balance.

M. tuberculosis infects host macrophages,” Carroll said. “These immune cells produce high levels of reactive oxygen and reactive nitrogen species (RONS), which cause oxidative damage to biomolecules, such as lipids, proteins and DNA. For this reason, M. tuberculosis depends heavily upon the production of RONS-neutralizing reduced sulfur compounds, including mycothiol and cysteine. This is why the reductive sulfur assimilation pathway is such a powerful target. Once you reduce the level of reduced sulfur compounds, you eliminate a central mechanism that all bacteria, including M. tuberculosis, use to survive host defense systems.”

The new study may encourage exploration of this pathway as a target for development of other antibacterial treatments.

"The first-in-class inhibitors in our study satisfy many criteria expected of a lead scaffold for anti-tuberculosis therapeutics,” said Prakash Palde, the first author of the study and a research associate in the Carroll lab. “But the presence of APSR enzyme in other pathogenic bacteria also means our new inhibitors may have the potential to be developed in to a class of broad-spectrum antibiotics.”

In addition to Carroll and Palde, other authors of the study, “First-In-Class Inhibitors of Sulfur Metabolism with Bactericidal Activity against Non-Replicating M. tuberculosis,” include Laura E. Pedró Rosa, Franck Madoux, Peter Chase, Vinayak Gupta, Timothy Spicer and Louis Scampavia of TSRI; and Ashima Bhaskar and Amit Singh of the Indian Institute of Science, Bangalore, India. For more information, see https://pubs.acs.org/doi/abs/10.1021/acschembio.5b00517

The work was supported by the National Institutes of Health (grant number GM087638), the Ministry of Science and Technology, India (BT/PR5020/MED/29/454/2012), and the Wellcome-DBT India Alliance (500034/Z/09/Z).
_________
FOR MORE INFORMATION
Kate Carroll Biosketch
The Carroll Lab
ACS Chemical Biology paper

This article was originally published on www.scripps.edu.
About the Author
  • The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists-including two Nobel laureates-work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
You May Also Like
SEP 09, 2020
Microbiology
Changing How We Think of Drug Resistance in Fungi
SEP 09, 2020
Changing How We Think of Drug Resistance in Fungi
It's been estimated that fungal infections cause more than one million deaths worldwide, and many more are affected.
SEP 09, 2020
Cell & Molecular Biology
Why Liver Gene Therapies Have Not Worked & How to Improve Them
SEP 09, 2020
Why Liver Gene Therapies Have Not Worked & How to Improve Them
Diseases that are caused by errors in a gene might be cured if we could correct those errors, or genetic mutations.
OCT 05, 2020
Plants & Animals
Bacteria Caused the Deaths of Hundreds of Elephants
OCT 05, 2020
Bacteria Caused the Deaths of Hundreds of Elephants
African elephants are a threatened species that are increasing in some areas but at risk in many others. There are proba ...
OCT 12, 2020
Genetics & Genomics
The Malaria Parasite Can Change Host Cell Genetics
OCT 12, 2020
The Malaria Parasite Can Change Host Cell Genetics
Mosquitoes can transmit the malaria-causing Plasmodium parasite to humans. Malaria was estimated to have caused the deat ...
NOV 08, 2020
Microbiology
Seasonal Illness - Is the Sun Involved?
NOV 08, 2020
Seasonal Illness - Is the Sun Involved?
There is a cold and flu season, and many researchers have tried to explain why the viruses that cause these illnesses te ...
NOV 17, 2020
Drug Discovery & Development
Antibiotics Before Age 2 Linked to Childhood Health Conditions
NOV 17, 2020
Antibiotics Before Age 2 Linked to Childhood Health Conditions
Researchers from Mayo Clinic have found a link between children aged two and under taking antibiotics and an increased r ...
Loading Comments...