The Bill & Melinda Gates Foundation has awarded two grants totaling $6.8 million to academics at Weill Cornell Medicine and the TB treatment Accelerator to examine tuberculosis (TB) treatment development. Two major roadblocks in tuberculosis drug development will be accelerated by this effort: discovering novel lead chemicals and new therapeutic targets within the bacteria.
Chest pain, fever, and cough are symptoms of Mycobacterium tuberculosis (Mtb), a pathogen that multiplies in the lungs after infection. TB is still one of the most deadly infectious illnesses, despite its high contagiousness. Worldwide, 10.6 million people got the illness last year, and the World Health Organisation estimates that 1.3 million people died as a result.
Taking many antibiotics for up to nine months is necessary for Tuberculosis treatment. “We could treat Tuberculosis much better in the regions where the disease takes its biggest toll, if we could shorten the time patients need to take antibiotics and discover more effective medications,” said Dr. Schnappinger.
Mtb’s ability to adapt to various environments inside the human body makes it tough to eradicate since it can avoid treatment through drug resistance and drug tolerance. Drug resistance develops when patients stop taking their prescribed medications, mainly because of spontaneous gene alterations that make the bacteria resistant to standard Tuberculosis medications. When bacteria experience a physiological alteration that enables them to withstand therapy that would ordinarily kill them, drug tolerance develops.
Seeking For Novel Small-Molecule Medications
Identifying which small compounds from the Tuberculosis Drug Accelerator should be developed further is one of Dr. Schnappinger’s research objectives. His group is investigating how these tiny compounds can either kill or stop the growth of Mtb utilising genetic techniques. Finding many molecules with distinct functions would be advantageous in the fight against drug resistance.
The Mtb mutant libraries, which comprise 30,000 to 100,000 strains, are used to test the small compounds. These strains were created in cooperation with Dr. Jeremy Rock, who oversees the Laboratory of Host-Pathogen Biology at Rockefeller University. Different genes are underexpressed in different bacterial strains, resulting in reduced production of that protein. The underexpressed gene can be identified as the weak point of the bacterium by researchers when a small substance destroys or slows the growth of a specific strain of Mtb.
Testing the small molecules on a Mtb overexpression library—a collection of roughly 1,000 Mtb strains—that is intended to produce excessive amounts of a necessary gene product is an alternative strategy. If a tiny molecule’s target is overexpressed, it would cease to impede the growth of a strain. “Profiling small molecules with both knockdown and overexpression libraries allows us to better predict the direct target of a small molecule,” he stated.
In addition, in order to comprehend how mutations make the bacteria immune to the medication, the researchers are separating Mtb mutants that are resistant to the tiny chemicals under investigation.
Through the use of a multifaceted approach, light is being cast on the ways in which the small molecules of interest impede the growth of Mtb, as well as any potential toxicities and other structurally related molecules that might be more potent. When the data is combined, it aids researchers in making decisions about which compounds to pursue further for potential therapeutic development.
Reducing The Duration Of Tuberculosis Treatment
Efforts to reduce the length of Tuberculosis treatment are supported by the second award. Since the current medications were created to prevent Mtb from proliferating, it should come as no surprise that they are less effective against dormant or non-growing Mtb strains. Granulomas, for instance, are white blood cell clusters with a core of dying cells that are indicative of tuberculosis. The fact that the bacteria inside the granuloma frequently stop growing and become resistant to existing pharmacological treatments is probably one of the reasons why patients take so long to recover. “Identifying drugs that are more effective against this Mtb population is expected to shorten treatment,” he stated.
The goal of this research is to pinpoint medication targets, such as those inside granulomas and drug tolerance, that are essential to Mtb survival during infections. Antibodies made to block certain targets might act more quickly and offer effective combo therapies.
Researchers at Weill Cornell Medicine have worked together to accomplish this ambitious project, according to Dr. Schnappinger. These include Dr. Carl F. Nathan, chair of microbiology and immunology; Dr. Kyu Y. Rhee, professor of microbiology and immunology and professor of medicine; and Dr. Sabine Ehrt, professor of microbiology and immunology and co-head of the graduate programme in immunology and microbial pathogenesis. Additionally involved in this endeavour was Dr. Michael Glickman from the Sloan Kettering Institute.
“One of our main goals is to extend this work to TB animal models, which will allow us to evaluate drug targets in the context of an infection,” stated Dr. Schnappinger. “Ultimately, we want to find the Achilles heel of this pathogen.”
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