6-azasteroids with unique activity in mycobacteria

Background

One third of the world’s population is infected with tuberculosis (TB). In 2014, there were 1.5 million TB related deaths. There are drugs to combat the bacteria by attacking the bacteria directly. The current recommended treatment regimen for TB begins with a two-month intensive therapy using isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of treatment with isoniazid and rifampicin. The issue is that drugs like isoniazid lose their efficacy over time. As an alternative, bedaquiline has stepped in with a new approach to handle TB. Bedaquiline is designed specifically to target mycobacterial adenosine triphosphate synthase. This enzyme is produced by the mycobacteria and is essential for the supply of energy to the mycobacterium tuberculosis and other bacteria in the same family. The issue is that the drug is expensive for a full 6 month treatment process and depending on the person undergoing treatment, may not be enough on its own.

Technology

New variations of 6-azasteroids have improved the ability to aid bedaquiline and lessen the amount necessary for tuberculosis treatment. Tuberculosis uses the host body’s sterols, such as cholesterol, to reproduce. Normally the body would regulate cholesterol levels with testosterone, but testosterone is often transformed into dihydrotestosterone by 5a-reductase. 6-azasteroids can inhibit 5a-reductase, which leaves testosterone to lower the amount of cholesterol in the body. This starves the tuberculosis, relieving much of the strain on bedaquiline. The drug can now target the bacteria located at other sterols, such as the glycerols which are vital for other bodily functions. 6-azasteroids have been cited for their low toxicity and ability to be spread throughout the body with little to no issues from side effects when tested in rats and dogs. The 6-azasteroids may be a promising supplemental treatment for those undergoing tuberculosis treatment, and can possibly lead to faster recovery with less use of current on the market drugs.