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News & Events
[World TB Day 2022] Invest to End TB. Save Lives.
2022-03-24
World TB Day 2022 ‘Invest to End TB. Save Lives.’
Every year Mar 24 is World Tuberculosis (TB) Day. We commemorate the day with broad activities to raise public awareness about TB and to gather broader efforts to end the global TB epidemic. The date marks the day in 1882 when Dr. Robert Koch announced his discovery of the bacterium that causes TB, which opened the way towards diagnosing and curing this disease.
WHO set the theme of World TB Day 2022 as ‘Invest to End TB. Save Lives.’ with the aim of conveying the urgent need to invest resources to ramp up the fight against TB and achieve the commitments to end TB made by global leaders.
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Source: WHO Homepage
About TB
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In the years since the discovery of Mycobacterium tuberculosis (Mtb) in the 19th century, TB has continued to be a problem for human health, with an estimated 1.4 million deaths annually.
(Image on the right: Mtb in the macrophage (Source: Institut Pasteur)
Mtb itself is a unique intra-cellular pathogen, which can persist latently for years without causing illness of damage to the host. However, in the event of lung trauma, either physical or pathogenically (COVID-19, Influenza) the bacterium can activate leading to severe disease.
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Because of delayed diagnosis, and with length treatment programs and inefficient vaccine protection, the world wide problem of TB is only made worse with the emergence of drug and multi-drug resistant strains. In 2021, the WHO reported that 71% of TB cases were resistant to Rifampicin, the current antibiotic of choice for treatment.
If the ambitious WHO goal of ending the TB pandemic by 2030 is to have any chance of success, then new therapeutic targets, drugs, and vaccines must be identified and developed.
Institut Pasteur Korea is tackling TB by identifying new targets and innovative therapies.
Institut Pasteur Korea (IPK) is standing at the forefront of the global war against TB by establishing multidimensional strategies and collaborating with the leading organizations, including TB alliances, and individual research groups.
In particular, the IPK’s Medicinal Chemistry Team (MC) and Tuberculosis Research Lab (TRL) focus on identifying new molecules active against Mtb that are based on new targets to overcome the challenges of current therapeutic options.
1) IPK’s Medicinal Chemistry professionals identified new targets using chemoinformatics.
Conducted a government-supported TB project in collaboration with domestic institutes
The IPK’s MC was granted the Ministry of Health and Welfare's 2020 infectious disease prevention and treatment technology development grant, and has successfully conducted in development of novel anti-tuberculosis compound over the past two years in collaboration with the International Tuberculosis Research Center (ITRC) and The Korean Institute of Tuberculosis (KIT).
Leveraging chemoinformatics in identifying new targets & inhibitors
Through this program, first of all, a new protein target was selected based on the tuberculosis resistance mutation database built by analyzing and profiling the resistance mutations from clinically separated drug-sensitized and multidrug-resistant M. tuberculosis bacteria. Afterwards, compounds were virtually explored based on the 3D structures of the selected target proteins, and candidate compounds that inhibit tuberculosis were selected through efficacy evaluation of the selected candidate compounds based on the docking results.
(Image on the right: Mtb in the macrophage (Source: Institut Pasteur)
Mtb itself is a unique intra-cellular pathogen, which can persist latently for years without causing illness of damage to the host. However, in the event of lung trauma, either physical or pathogenically (COVID-19, Influenza) the bacterium can activate leading to severe disease.
Because of delayed diagnosis, and with length treatment programs and inefficient vaccine protection, the world wide problem of TB is only made worse with the emergence of drug and multi-drug resistant strains. In 2021, the WHO reported that 71% of TB cases were resistant to Rifampicin, the current antibiotic of choice for treatment. If the ambitious WHO goal of ending the TB pandemic by 2030 is to have any chance of success, then new therapeutic targets, drugs, and vaccines must be identified and developed.
Institut Pasteur Korea is tackling TB by identifying new targets and innovative therapies.
Institut Pasteur Korea (IPK) is standing at the forefront of the global war against TB by establishing multidimensional strategies and collaborating with the leading organizations, including TB alliances, and individual research groups.
In particular, the IPK’s Medicinal Chemistry Team (MC) and Tuberculosis Research Lab (TRL) focus on identifying new molecules active against Mtb that are based on new targets to overcome the challenges of current therapeutic options.
1) IPK’s Medicinal Chemistry professionals identified new targets using chemoinformatics.
Conducted a government-supported TB project in collaboration with domestic institutes
The IPK’s MC was granted the Ministry of Health and Welfare's 2020 infectious disease prevention and treatment technology development grant, and has successfully conducted in development of novel anti-tuberculosis compound over the past two years in collaboration with the International Tuberculosis Research Center (ITRC) and The Korean Institute of Tuberculosis (KIT).
Leveraging chemoinformatics in identifying new targets & inhibitors
Through this program, first of all, a new protein target was selected based on the tuberculosis resistance mutation database built by analyzing and profiling the resistance mutations from clinically separated drug-sensitized and multidrug-resistant M. tuberculosis bacteria. Afterwards, compounds were virtually explored based on the 3D structures of the selected target proteins, and candidate compounds that inhibit tuberculosis were selected through efficacy evaluation of the selected candidate compounds based on the docking results.
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Result of binding mode docking target protein x-ray structure (A. WT structure; B. mutant structure) and POM active materialFinally, the derivatives of selected POM scaffold was designed and synthesized based on SAR/SPR activities through the evaluation of tuberculosis inhibitory activity to derive the first-in-class effective compound as an anti-tuberculosis agent. We have secured intellectual property rights for POM scaffold through Korean patent application. In addition, the new POM scaffold showed inhibitory effects on liquid medium M. tuberculosis and M. tuberculosis in macrophages, and confirmed the inhibitory effect of M. tuberculosis in clinical M/XDR strains.
Lead Optimization in progress to develop a new anti-tuberculosis agent that inhibit drug-susceptible as well as drug-resistant M. tuberculosis
These research results could be the breakthrough in developing new drugs for tuberculosis in such a way to select clinically meaningful targets based on genetic information of drug-susceptible and resistant clinical M. tuberculosis strains. By using such Structure-based Drug Design (SBDD) method, the effect of M. tuberculosis gene targets that affect resistance to tuberculosis drugs is predicted, and more drug targets can be predicted without going through intensive experiments. We can overcome the limitations of developing therapeutics. The Medicinal Chemistry team is focusing on the optimization of the new POM scaffold’s lead compound with the aim of developing a new anti-tuberculosis agent that inhibit drug-susceptible as well as drug-resistant M. tuberculosis.
2) IPK’s TB specialists are investigating the folate pathway of mycobacteria.
Blocking Mycobacterium tuberculosis Folate Pathway
Folate is an essential vitamin that is familiar to us as vitamin B9. Folate is used by all cells and needs to be obtained for the continued life cycle of the cell.
In eukaryotes (i.e humans), folate cannot be produced and therefore is obtained via diet. However in prokaryotes (i.e Mtb) folate can be produced via biosynthesis, removing the need to directly obtain it from nutrition. This biosynthesis occurs via the folate pathway, which involves multiple reactions catalyzed with distinct enzymes to ultimately produce the active form of folic acid, tetrahydrofolate (THF). These enzymes make for perfect targets for Mtb therapeutics, as they do not exist in the host and disruption to the folate pathway will impair the growth of the bacteria.
THF (tetrahydrofolate) is the biologically active form of folate. Enzymes are shown in green, with known inhibitors in red. FolB and FolK, in blue are two potential targets of interest for us. (Figures created with BioRender.com)
Screening and Identification of FolB Inhibitor Candidates
One of these enzymes of interest to us is coded by the gene FolB, which is utilized relatively early in the folate biosynthesis pathway. FolB has been found to be essential for bacterial growth via deletion studies, where bacteria were unable to multiply without the gene.
To develop effective inhibitors of the FolB enzyme, the TRL first isolated and purified the native form of the enzyme, and developed an assay to monitor its activity by using fluorescence as an output. Using this system, researchers screened 9,000 compounds in the search for the ones that may be used to inhibit the enzyme and therefore have the potential for TB drug candidates. As a result, several hit compounds were identified. Derivatives were synthesized by the Medicinal Chemistry Team.
(Figures created with BioRender.com)
These hit compounds can then be further studied using dose-response assays, and work with live Mtb and drug-resistant strains and drug in IPK’s biosafety level 3 (BSL-3) laboratory with their effects being compared to current treatments.
Additional study targeting FolK and other enzymes for synergy with FolB
The additional enzymes in the folate biosynthesis pathway are also of interest for us, the enzyme coded by the FolK gene. This enzyme is involved in the reaction directly after that of FolB, so it could be used in combination with FolB in our screening assays to better improve potential hit generation.