Two Compounds Show Promise against Resistant Tuberculosis: Study
Wed, April 21, 2021

Two Compounds Show Promise against Resistant Tuberculosis: Study



Two compounds have been found with promising activity against tuberculosis. Both exhibited antibacterial properties and unlikely to be affected by resistance.

The two compounds with anti-tuberculosis activity were determined by researchers at John Innes Center (JIC), an independent research center in the UK. Their findings showed both compounds as antibiotic candidates for tuberculosis (TB). They tested the compounds for resistance and found both unaffected by mutations. If antibiotics could be derived from either of the compounds, it would help global efforts against TB. Results were published in the Journal of Antimicrobial Chemotherapy.


The 2019 Global Report on Tuberculosis

According to the World Health Organization (WHO) of the United Nations, TB is an infectious disease caused by a Mycobacterium group of bacteria. The disease is considered a top global killer due to its ability to induce deaths, either alone or together with another disease. TB alone has a higher death rate worldwide than HIV/AIDS. Although there are antibiotics for TB, these medications do not work in all cases because of resistance.

Certain strains have multidrug-resistance that renders the most effective first-line drug ineffective. As such, newer medications are needed to control TB epidemics. There is also a need for better therapies to address people with latent TB. Latent TB refers to people infected by the bacteria but are not ill and cannot transmit it to others. Approximately 25% of the world's population has latent TB, and if their immune system weakens, they may develop active TB.

In the Global Tuberculosis Report 2019, about 1.5 million people died from TB in 2018. Out of that, around 251,000 deaths were among people with HIV. And among people living with HIV, TB has been the greatest risk factor of untimely death. An estimated 10 million people worldwide were diagnosed with TB. About 5.7 million were men, 3.2 million were women, and 1.1 million were children. Despite the availability of TB vaccines, more efforts are required to better manage annual TB cases and deaths.

Drug-resistance TB strains remained a significant health issue. In 2018, 500,000 new cases of TB exhibited resistance to rifampicin, and 78% of those had multidrug resistance. The countries with the largest share of the global burden of resistant TB cases were India at 27%, China at 14%, and Russia at 9%.

When it comes to progress, the average rate of decline in TB incidence rate was 1.6% annually from 2000 to 2018, and 2% between 2017 and 2018. The cumulative reduction from 2015 to 2018 was 6.3%, lower than the targeted 20% of the End TB Strategy milestone. For deaths, the global decline was 11% between 2015 and 2018, also lower than the targeted 35% of the same milestone.

Regionally, the WHO European Region maintains its track to achieve the 2020 milestones. From 2015 to 2018, the incidence rate in the region dropped by 15% and the death rate fell by 24%. The WHO African Region also showed declines of 4.1% in incidence rate and 5.6% in death rate per year within the same period.



Two Compounds Could Lead to New Anti-TB Drugs

At JIC, researchers investigated compounds with anti-TB properties. They sought for new derivatives that could be turned in antibiotics in the future. Two compounds showed potential in countering TB without being affected by a common mutation, which often results in resistance. The compounds were Redx03863 and Redx04739 tested in antibacterial assays, according to the submitted paper.

"We hope that companies and academic groups working to develop new antibiotics will find this study useful. It opens the way for further synthesis and investigation of compounds that interact with this target," said Professor Tony Maxwell, the corresponding author of the study.

The potential of these compounds was confirmed in the examination of a known exploit. Existing drugs against TB would exploit the DNA gyrase, a bacterial enzyme in Mycobacterium. The enzyme is critical in the DNA functionality of TB bacteria. As such, inhibitors of the enzyme could stop the microbe. However, the enzyme could be influenced by mutations and render inhibitors useless.



Via x-ray crystallography, researchers clearly observed the molecular details of both compounds in action against TB bacteria. Results showed that the compounds were unaffected by a very common mutation in DNA gyrase. The said mutation could result in TB bacteria to resist a class of antibiotics called aminocoumarins. When the mutation occurred, the effects of the compounds persisted.

Furthermore, the two compounds were active in Gram-positive and Gram-negative TB bacteria species. Though, Redx03863 was more potent than Redx04739. Redx04739's potency was identified to be selective against M. smegmatis, a Mycobacterium species considered generally harmless. Redx03863 was also determined unaffected by resistant mutations and with a distinct binding site from novobiocin. These characteristics suggested possible ventures to formulate antibiotics from Redx03863, which could be used against TB and other resistant bacteria.

Prof. Maxwell explained that antimicrobial resistance is one of the biggest threats of the 21st Century. While the COVID-19 pandemic is the pressing issue due to its impact on the economy, resistance bacterial strains are not to be ignored. If these pathogens create an outbreak in COVID-19 cases, the healthcare system will be in direr situations. The human body can fight back the SARS-CoV-2 with antibodies and supportive care, as demonstrated by survivors, but drug-resistant bacteria are unmitigated by treatment. If a bacterium exhibits resistance to all antibiotics, it is impossible to treat.

Epidemics that are linked to antimicrobial resistance include the bubonic plague, the same disease that caused the Black Death in Africa, Asia, and Europe. If strains of Yersinia pestis can effectively resist doxycycline, gentamicin, and streptomycin, the annual cases of dozens to hundreds may balloon to thousands to hundreds of thousands. In a grim situation, the same resistant Y. pestis can share the resistance to other bacterial groups, enabling breeding of future superbugs.

At the moment, the reemergence of the bubonic plague in Inner Mongolia caught the attention of health authorities. Actions have been swift to contain new cases and stop a potential outbreak. Precautions are in place and monitoring continues to ensure the disease will not go out of control.