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New Treatment Fights Off TB Bacterium’s Resistance

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The reason why tuberculosis-causing bacteria can easily spread inside the body is because they evade the body's natural defenses. However, some researchers from Brown University have created a new compound that could block the 20S proteasome in Mycobacterium tuberculosis, the bacterium responsible for tuberculosis. The researchers hope that this compound can be a new remedy against tuberculosis.

According to the researchers, this study was started because of the fact that there is increasing resistance of drugs towards Mycobacterium tuberculosis. In the light of this, the researchers thought about a different form of treatment. Instead of seeking traditional drugs that claim to kill M. tuberculosis directly, they thought of discovering new compounds that could make the bacteria responsive to treatments and susceptible to the body's immune system. The team thinks that they are good in designing compounds that would make bacteria in the laboratory sensitive to a chemical that is produced during the immune response.

The researchers were from Brown University, Massachusetts Institute of Technology and Weill Cornell Medicine. Their study is published in the journal ACS Infectious Diseases.

The team wanted to develop a compound that can inhibit an enzyme found in M. tuberculosis known as the 20S proteasome. This enzyme is known to act like a garbage collector in cells that disposes damaged proteins inside cells. It also cleans up proteins that are damaged by nitric oxide, a chemical which is produced by the body's immune system to help fight against pathogens. This garbage-disposing property of the 20S proteasome for proteins that are brought about by nitric oxide damage can help the bacteria survive inside the cells of the body.

Inhibiting 20S proteasome

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The researchers looked for reactive compounds that are able to mimic key chemical attributes of its substrates which are typically broken down by the enzyme so that the proteasome can be inhibited. They are aware of the fact that the proteasome would bind these compounds as it would do with any protein and that when they react they would disable the enzyme. When the proteasome is disabled, the proteins that are damaged by nitric oxide will gather inside the bacteria and will cause the latter's death.

However, the researchers saw a potential problem. The human body has a conventional way of degrading damaged proteins and if this way is inhibited, it can cause more harm to cells. So, the researchers thought of ways on how to selectively disrupt the proteasome without affecting the human bodily process. To do this, the researchers thought about a bacterium called Pseudomonas syringae which affects plants. This bacterium produces compounds known as syringolins which are able to inhibit plant proteosomes by mimicking its substrates. Syringolins are also known to inhibit the human proteasome and are viewed as potential anti-cancer agents. The researchers predicted how these syringolins will bind with the human proteasome and designed selective inhibitors for the tuberculosis proteasome.

Previous studies have shown that syingolins are able to bind and inhibit the human proteasome by mimicking a substrate with a specific chemical residue, valine, at two key positions. These studies have also shown that the bacterial proteosome prefers to degrade proteins that have two different chemical residues at the same two key positions. So the researchers thought that if a syringoline analog is there to swap with valine for structures that resemble tryptophan and glycine, it would selectively inhibit the bacterial proteasome.

The team further added that the natural syringolin was 160 times more specific for the human proteasome. One of the engineered syringolin analogs was 47 times more specific for the bacterial proteasome.

Using this approach, the researchers were able to generate selective inhibitors of the M. tuberculosis 20S proteasome. This only shows that this strategy may be useful in combining tuberculosis treatments for more effective treatments.