Abstract
Cordycepin is an efficient component of Cordyceps spp, a traditional Chinese medicine widely used for healthcare in China, and has been recently acted as a strong anticancer agent for clinic. However, whether and how it may play a role in combating tuberculosis, caused by Mycobacterium tuberculosis, remains unknown. Here we report that cordycepin can kill Mycobacterium by hijacking the bacterial adenosine kinase (AdoK), a purine salvage enzyme responsible for the phosphorylation of adenosine (Ado) to adenosine monophosphate (AMP). We show that cordycepin is a poor AdoK substrate but it competitively inhibits the catalytic activity of AdoK for adenosine phosphorylation. Cordycepin does not affect the activity of the human adenosine kinase (hAdoK), whereas hAdoK phosphorylates cordycepin to produce a new monophosphate derivative. Co-use of cordycepin and deoxycoformycin, an inhibitor of adenosine deaminase (ADD), more efficiently kills M. bovis and M. tuberculosis. The add-deleted mycobacterium is more sensitive to cordycepin. This study characterized cordycepin as a new mycobactericidal compound and also uncovered a potential anti-mycobacterial mechanism.
Highlights
Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) and still globally threatens human health
Cordycepin can effectively prevent the growth of M. bovis BCG, M. tuberculosis H37Ra, and M. marinum M
No antibacterial activity was observed for the fast-growing M. smegmatis and non-mycobacterial species, including Escherichia coli, Staphylococcus aureus, and Bacillus thuringiensis, even the drug concentration was raised up to 12×minimum inhibitory concentration (MIC) of M. tuberculosis H37Ra
Summary
Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) and still globally threatens human health. In 2017, there were an estimated 10.0 million people fell ill with tuberculosis (TB), of which 457 560 had multidrug-resistant TB (MDR-TB) [1]. With the emergence of multidrugresistant (MDR) M. tuberculosis strains, new drugs are urgently needed for control of TB. Cordycepin was first isolated from the cultures of caterpillar fungus Cordyceps militaris, a well known Traditional Chinese Medicine widely used for healthcare in China [2]. This compound has been reported to have immunological regulation, antifungal, anti-virus, anti-leukemia, anti-inflammatory and antimetastatic effects [3,4,5,6,7,8,9,10].
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