Skip to main content

New Compound Excels at Killing Persistent and Drug-Resistant Tuberculosis



June 17, 2013 — An international team led by scientists at The Scripps Research Institute (TSRI), the Howard Hughes Medical Institute and Albert Einstein College of Medicine of Yeshiva University has identified a highly promising new anti-tuberculosis compound that attacks the tuberculosis (TB) bacterium in two different ways.

Share This:
"These findings represent an effort to help solve one of the major global health crises of our time -- the resurgence of TB and its dangerous drug-resistant strains," said Peter G. Schultz, the Scripps Family Chair Professor of Chemistry at TSRI, who was senior author of the study with William R. Jacobs, Jr., member of the Howard Hughes Medical Institute and professor of microbiology & immunology and of genetics at Albert Einstein College of Medicine.
"In cell cultures and in mice, this compound showed powerful activity against ordinary active TB bacteria, non-replicating TB bacteria and even extensively drug-resistant TB strains," said Feng Wang, a member of the Schultz lab at TSRI and first author of the study with Dhinakaran Sambandan of the Jacobs lab and Rajkumar Halder of the Schultz lab.
The paper appears in this week online ahead of print in an Early Edition of the Proceedings of the National Academy of Sciences.
Global Health Crisis
Although isoniazid and rifampin, the two front-line TB drugs, came into use in 1952 and 1967 respectively, new TB infections still occur at the rate of roughly one per second. At any moment about a third of the existing human population is infected -- mostly with inactive, latent TB, although active TB still kills over one million people each year. Russia, Africa, China and Southeast Asia have been especially hard hit by the epidemic.
Increased urbanization, public health complacency and immunity-weakening HIV have been major enablers of TB's spread in recent decades. But the bacterium that causes TB --Mycobacterium tuberculosis (Mtb) -- also happens to be unusually well adapted for persisting in humans. Among other strategies, it frequently reverts to a dormant, non-replicating state and also creates attack-resistant cell colonies called biofilms, which contain a high proportion of non-replicating TB.
Compared to ordinary, fast-replicating TB, these other forms of TB are much less susceptible to existing drugs. Effective TB therapy thus requires months to years of regular dosing. But many patients quit before completing such long courses of treatment and end up incubating drug-resistant TB strains. Some strains are now "extensively drug-resistant" (XDR) and virtually untreatable -- and usually fatal.
Killing the Persisters
"The big challenge here has been to find a drug that clears TB infection more quickly, which means it has to be effective against both replicating and non-replicating TB," said Wang, now also a scientist at the California Institute for Biomedical Research (CALIBR), a non-profit organization founded by Schultz for the early-stage development of new medicines.
Most existing TB drugs work poorly against non-replicating TB, having been developed principally for their ability to kill actively replicating TB. Wang therefore set up a different kind of screening test -- one to detect compounds that block TB's persistence-related ability to form biofilms.
Because experiments with live TB require a special (level 3) biosafety facility, Wang used a related but non-disease-causing mycobacterium for his initial, high-throughput test. Screening a diverse library of 70,000 compounds, he quickly found one, dubbed TCA1, that stood out for its ability to inhibit mycobacterial biofilms.
Tests in Jacobs's biosafety level 3-certified laboratory confirmed that TCA1 also has powerful activity against TB. "Surprisingly, it turned out to kill both non-replicating and replicating TB," Wang said.
In cell culture tests, TCA1 on its own killed more than 99.9% of ordinary, actively replicating TB bacteria within three weeks, and in combination with isoniazid or rifampin, could kill 100% within that period. TCA1 also showed strong effectiveness against drug-resistant TB strains, removing all signs of one common strain within a week when combined with isoniazid. Against a highly fatal "super-bug" strain from South Africa, which resists all conventional TB drugs, the new compound on its own had a kill rate of more than 99.999% within three weeks.
As expected, TCA1 also showed potent effects against non-replicating TB. Tests in mice confirmed TCA1's effectiveness and suggested that the combination of TCA1 and isoniazid could be more powerful than existing drug regimens. TCA1 showed no sign of toxicity or adverse side effects in cell culture and mouse experiments, and also showed almost no tendency to induce drug resistance in TB.
A Complex Mechanism
Working with the laboratories of Gurdyal S. Besra and Klaus Fütterer at the University of Birmingham, UK, Katarina Mikusova at Comenius University in Slovakia, and Kai Johnson at Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, the team next did structural and biochemical analyses to determine how the new compound kills Mtb so efficiently.
The researchers found it works in an apparently unique way, largely by targeting two Mtb enzymes, one supporting TB replication and the other TB dormancy and persistence. "I don't know of any other antibiotic that kills replicating bacteria through one pathway and non replicating bacteria through another, as this one does," Wang said.
Now funded by the Global Alliance for TB Drug Development, Wang and his colleagues are working to devise improved variants of TCA1. "We already have analogs of TCA1 that are more potent and look very promising as TB drug candidates," said Wang.
Assuming that preclinical tests are completed successfully, he added, the group hopes to find a pharmaceutical company partner to sponsor clinical trials in TB patients.
The study was funded in part by the National Institutes of Health (grants AI26170 and A10-97548), the European Community's Seventh Framework Programme (260872), the Global Alliance for TB Drug Development and the Albert Einstein College of Medicine Center for AIDS Research (AI0-51519).


Story Source:
The above story is reprinted from materials provided byScripps Research Institute.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:
  1. Feng Wang, Dhinakaran Sambandan, Rajkumar Halder, Jianing Wang, Sarah M. Batt, Brian Weinrick, Insha Ahmad, Pengyu Yang, Yong Zhang, John Kim, Morad Hassani, Stanislav Huszar, Claudia Trefzer, Zhenkun Ma, Takushi Kaneko, Khisi E. Mdluli, Scott Franzblau, Arnab K. Chatterjee, Kai Johnson, Katarina Mikusova, Gurdyal S. Besra, Klaus Fütterer, William R. Jacobs, Jr., and Peter G. Schultz. Identification of a small molecule with activity against drug-resistant and persistent tuberculosisPNAS, 2013 DOI: 10.1073/pnas.1309171110

Comments

Popular posts from this blog

ក្រមសីលធម៌ឱសថការី

ក្រមសីលធម៌ឱសថការី ១​​.​ និយមន័យក្រមសីលធម៌វិជ្ជាជីវៈឱសថ? ចំ​​ៈ គឺជាកាតព្វកិច្ចដែលឱសថការីត្រូវបំេពញ ចំពោះអតិថិជន សហការី អ្នកផ្តល់សេវា​ខាភិបាល និស្សិត វិជ្ជាជីវៈ និង​ អាជ្ញាធរមានសមត្ថកិច្ចក្នុងការអនុវត្តវិជ្ជាជីវៈឱសថ។​ ២. លក្ខណៈខុសគ្នារវាង ក្រមសីមធម៌វិជ្ជាជីវៈ​ និង​និតិក្រម? ចំៈ​ មាន៣ចំនុចៈ - ការរៀបចំ៉ ( development) ៖ ក្រមសីលធម៌ត្រូវបានរៀបចំដោយគណៈឱសថការីកម្ពុជា ( pharmacy professional ethic) រីនិតិក្រមត្រូវបានរៀបចំដោយស្ថាប័ននិតិបញ្ញត្តិ ឬស្ថាប័ននិតិប្រតិបត្តិ - ដែននៃការអនុវត្ត ( the field of implementation) ៖ ក្រមសីធម៌វិជ្ជាជីវៈត្រូវអនុវត្តចំពោះតែឱសថការីណាដែលប្រកបវិជ្ជាជីវៈឱសថ រីនិតិក្រមត្រូវអនុវត្តចំពោះរូបវ័ន្តបុគ្គល ( Physical person) និងនិតិបុគ្គល (ស្ថាប័នឬក្រសួង.. ) - ទោសបញ្ញត្តិ ការប្រព្រឹត្តល្មើសនិងក្រមសីលធម៌វិជ្ជាជីវៈ​​ ត្រូវទទួលទោសដែលមានលក្ខណៈជាអង្គការវិន័យ​ ដែលវិនិច្ឆ័យដោយ ក្រុមប្រឹក្សាគណៈឱសថការី​ ដូចជាការស្តីបន្ទោស ការប្រមានជាលាយ លក្ខអក្សរ ការផ្ជួរសមាជិកភាពជាបណ្តោះ អាសន្ន និង​ការដកហូតសមាជិកភាពជាអចិន្ត្រៃ៌។​ រីការប្រព្រឹត្តល្មើសនិងនិតិក្រមត្រូវផ្តន្ទាទោសដែលមានលក្ខណៈជា

The major events in Inflammation

This is the animation of acute inflammation response: 

ការផ្តល់ដង្ហើមសិប្បសិម្មិត

របៀបផ្តល់ដង្ហើមសិប្បនិមិ្មត អ្នកនឹងអាចជួបនូវហេតុការណ៌ជាយថាហេតុដែលតម្រូវអោយអ្នកធ្វើការសង្គ្រោះជនរងគ្រោះជា បន្ទាន់តាមដែលអ្នកអាចធ្វើ​ បាន! ការរផ្តល់ដង្ហើមសិប្បនិម្មិត គេអាចធ្វើសូម្បីតែនៅពេលជនរងគ្រោះនៅដង្ហើមខ្សោយផ្តឹកៗមិនទាន់ ដាច់ខ្យល់ក៏អាចធ្វើបានដែរ។​ នៅពេលអ្នកផ្តល់ដង្ហើមសិប្បនិម្មិត អ្នកត្រូវផ្លុំខ្យល់ដង្ហើមចេញអោយ ស្របនិងការដកដង្ហើមរបស់ជនរងគ្រោះ។​ ជំហានទី១ ·        ដាក់ជនរងគ្រោះអោយដេកផ្ងា មុខឡើងលើ ·        ការឆ្លើយតប-តើជនរងគ្រោះដឹងខ្លួនរឺទេ? ·        ពិនិត្យមើលចលនាដើមទ្រូងដាក់ត្រចៀករបស់អ្នកលើមាត់របស់ជនរងគ្រោះ ដើម្បីពិនិត្យមើលដង្ហើម។​ ·        ហៅរកជំនួយ។​ ជំហានទី២ លើកចង្កាឡើង បើសិន ក​ ជនរងគ្រោះគ្មានរបួស ·        ផ្អៀងក្បាលជនរងគ្រោះដើម្បី “ ហិតក្លិន ” (មានក្លិនអ្វីចេញមករឺទេ) ដោយយកដៃម្ខាង ទៀតទ្រ ក របស់គាត់ចុះ ក្រោម។​ ·        សង្កត់អណ្តាត និង​ចង្ការបស់ជនរងគ្រោះនៅចន្លោះម្រាមដៃរបស់អ្នក រួចជូតសំអាត វត្ថុដែលនៅជាប់ក្នុងមាត់របស់គាត់ចេញដោយប្រើម្រាមដៃ និង កូនកន្សែងដៃហើយ ពិនិត្យមើលអណ្តាតរបស់គាត់កុំឲធ្លាក់ទៅក្រោយ។​ ជំហានទី៣ ច្របាច់ច្រមុះជនរងគ្រោះឲជិតរួចដកដង្ហើមរបស់អ្នកឲវែង ដាក់មាត់របស់