Researchers have discovered a compound found in soil bacteria that could lead to new drugs to combat tuberculosis, a global disease that is becoming increasingly resistant to current treatments. They have produced synthetic versions of the natural compound and showed that they can kill the tuberculosis bacterium in the laboratory.
The findings, published in the journal Nature Communications, are the work of an international consortium led by the University of Sydney in Australia and includes researchers from the United Kingdom, the United States, and Canada.
Tuberculosis (TB) is a disease caused by the bacterium Mycobacterium tuberculosis. While it can affect any organ of the body, it is most commonly found in the lungs. Most cases are treatable and curable, but people can die if they do not receive proper treatment.
According to the World Health Organization (WHO), TB is globally one of the top 10 causes of death: 10.4 million people became ill with it and 1.8 million people died from it in 2015. Over 95 percent of TB-related deaths affect low- and middle-income countries.
Huge progress has been made in the global fight against TB. The WHO report that 49 million lives were saved through effective diagnosis and treatment between 2000 and 2015.
However, there is a growing threat to continuing this progress, in that the TB bacterium is becoming increasingly resistant to the current drugs available to treat it – many of which have been in use for more than 40 years.
- In 2015, around 480,000 cases of TB were MDR-TB
- Estimates suggest that more than 250,000 deaths were due to drug-resistant TB
- China, India, and the Russian Federation account for nearly half of global MDR-TB cases.
There are two forms of drug-resistant TB: multidrug-resistant (MDR-TB), and the much rarer form, extensively drug-resistant TB (XDR-TB).
MDR-TB is resistant to at least isoniazid and rifampin, two potent first-line drugs used to treat everyone who falls ill with TB.
XDR-TB is resistant to isoniazid and rifampin, any fluoroquinolone, and at least one second-line drug, leaving patients with few effective treatment options.
In the U.S., the average direct cost of treating TB ranges from $18,000 to treat drug-susceptible forms, to $494,000 to treat XDR-TB.
These costs are even higher when they take into account income losses experienced by patients while undergoing treatment.
The new study concerns a compound called sansanmycin uridylpeptide, which is produced by soil bacteria and stops other bacteria growing around them.
The team used synthetic chemistry to produce a library of more potent structural variations, or analogs, of the natural compound.
Laboratory tests showed that the sansanmycin natural product analogs were effective killers of M. tuberculosis, the bacterium that causes TB.
The compounds target an enzyme called Mtb phospho-MurNAc-pentapeptide translocase, or MraY, which plays a key role in building the cell wall of the TB bacterium.
Attacking this “Achilles heel” of the bacterium prevents it from being able to build a cell wall.
Richard Payne, a professor in Sydney’s School of Chemistry and one of the lead investigators, says that the new analogs effectively killed the TB bacteria inside macrophages – the host immune cells that TB bacteria inhabit when they infect human lungs.
Prof. Payne says that their findings offer a starting point for developing a new TB drug, and that further tests and safety studies are already being planned.
Future work will also explore the underlying mechanism through which the new compounds select their target, note the authors.
“Without a cell wall, the bacterium dies. This wall-building protein is not targeted by currently available drugs.”
Prof. Richard Payne