As one of the top ten leading causes of death in the world, tuberculosis (TB) remains a persistent threat to public health. With drug resistance to this deadly pathogen on the rise, the quest for new drug targets and compounds is more critical than ever. Now, a team of scientists led by investigators at the University of Sydney has just published data about their recent findings that show antibacterial compounds found in soil could lead to the development of new treatments for TB.
The findings from this new study were published recently in Nature Communications through an article entitled “Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.
Low incidence rates of TB in industrialized countries has often lead to the notion that the disease is a relic of past centuries and not a major global health threat. Yet, by the end of 2015, there were an estimated 10.4 million new cases of TB worldwide and 1.8 million deaths. And while the global number of TB deaths has fallen 22% over the past 15 years, microbial resistance has been on the rise, with over 500,000 of new cases having some level of resistance to commonly used drugs to fight the disease.
Since Mycobacterium tuberculosis—the bacterium that causes TB—has become increasingly resistant to current therapies, there is an urgent need to develop new TB drugs. The Australian scientists set out to find novel compounds that could be effective at killing this devastating pathogen.
“We describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads,” The authors wrote. “The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria.”
The group was drawn to soil bacteria compounds known to effectively prevent other microbes growing around them. Using synthetic chemistry, the researchers were able to recreate these compounds with structural variations, turning them into more potent compounds called analogs. When tested in a containment laboratory these analogs proved to be effective killers of M. tuberculosis.
“These analogs inhibit the action of a key protein needed to build a protective cell wall around the bacterium,” explained senior study investigator Richard Payne, Ph.D., professor of chemistry at the University of Sydney, Australia. “Without a cell wall, the bacterium dies. This wall-building protein is not targeted by currently available drugs. The analogs also effectively killed TB-causing bacteria inside macrophages, the cells in which the bacteria live in human lungs.”
While the researchers were excited by their initial findings as the starting point for a new TB drug design, they also realized that their work is still preliminary and will require further testing and safety studies. “This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis,” the authors concluded.