SMARt751 Brings a Solution to Drug Resistance by Tuberculosis Bacteria in Animal Models

Infection with Mycobacterium tuberculosis leads to the development of tuberculosis. It is transmitted from persons with active tuberculosis to others through air droplets. The lungs are the most affected organ, though, other organs of the body can be affected too. When the organism enters the bloodstream, it causes miliary tuberculosis.

Tuberculosis

Tuberculosis

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On the entrance of Mycobacterium tuberculosis into a human host through air droplets, it replicates inside the lungs. It has an affinity for the lower part of the lung’s upper lobe. It can also be found in the upper part of the lung’s lower lobe. Macrophages attack this organism but cannot eliminate it due to its acid capsule. The infected macrophage attracts other macrophages and phagocytes.  If the organism keeps replicating even with the aggregates of these immune cells and gets to the hilar lymph nodes, a Ghon’s complex is formed.

In latent TB, the body can prevent the further spread of the organism. Hence, the organism cannot be spread even though present. In cases where the immune system is suppressed, there can be reactivation of the infection.

When the infections get to the lung parenchyma and airways, the person can transmit the disease through coughing and sneezing. Such a person is said to have developed active tuberculosis.

A diagnosis of tuberculosis can be made using tuberculin skin tests. A swelling of about 15mm or more after about 48 to 72 hours of tuberculin injection shows a positive test. Blood tests, sputum culture, and chest X-rays can help confirm the diagnosis. Clinical symptoms like weight loss, fever, drenching night sweats, and coughing are also helpful in making a diagnosis.

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Multi-drug regimen used in TB management

Tuberculosis is one of the diseases that is treated with a multidrug regimen. Monotherapy can lead to drug resistance. Hence, a group of four drugs is used for TB treatment in the first two months, the intensive phase. They include isoniazid, rifampicin, ethambutol and pyrazinamide. The continuation phase of TB treatment involves taking Rifampicin and Isoniazid for the next four months after the intensive phase.

There is a modification to TB treatment when the organism is resistant to isoniazid, rifampicin, and other TB drugs. This type of resistant TB is known as multi-drug resistant TB (MDR-TB). This is due to the evolution of the microorganisms. MDR-TB is treated for a longer duration, 15-24 months, with the intensive phase lasting for 5-7 months. Drugs used here include levofloxacin, bendaquiline, linezolid, clofazimine, streptomycin, and ethionamide among others.

Unfortunately, these organisms have started developing resistance against these antibiotics used in the treatment of MDR-TB too. This poses a serious threat to future treatments, so, it should not be neglected. Hence, the research on Mycobacterium tuberculosis resistance to ethionamide by Marion Flipo and team.

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The effect of SMARt751 on mycobacterium

It was discovered that the organism converts the prodrug, ethionamide, into an active form through one of its enzymes, MmyA. The active form of the drug in turn kills the bacteria. Hence, the bacteria help in its killing. However, with evolution, some of these organisms have acquired genes that help them in repelling ethionamide, making the drug ineffective.

To solve this puzzle, the team started trying out molecules that can help prevent this resistance. They found out that the molecule, SMARt751 reacts with VirS, a transcriptional regulator of the MmyA operon of mycobacterium. This causes the bacterium to be susceptible to Ethionamide again. This research was carried out in mice with acute and chronic TB. The molecule was found to be safe and effective in killing the organism both in vitro and in vivo.

It is predicted that a daily dosage of as little as 25 mg of SMARt751 may increase Ethionamide effectiveness in humans fourfold. This promising discovery calls for further research and clinical trials.

Clinical significance

Tuberculosis one of the killer diseases is treated with a multidrug regimen to prevent the development of resistance. However, evolution has favored the mycobacterium and over time, it has developed resistance even against the drugs used to treat MDR-TB.

Hence, this study was conducted to bring a solution to this dilemma. The molecule, SMARt751, has helped in reversing the resistance of the mycobacterium to ethionamide in mice models. It has also been proven to be safe for these animals. However, a need for clinical trials remains.

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Conclusion

In mice, SMARt751 has helped in increasing the effectiveness of ethionamide against Mycobacterium, altering its resistance. The safety of the molecule, SMARt751, in these animal models is an added benefit. With clinical trials, this molecule can help to reduce the dosing and side effects of the drug, ethionamide while increasing its potency.

References

The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis

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