r tb :: Article CreatorTB Under The Sea: A Marine Sponge Microbe Provides Insights Into The Evolution Of Tuberculosis
The surprising discovery of a bacterium in a marine sponge from the Great Barrier Reef with striking similarity to Mycobacterium tuberculosis, the pathogen responsible for tuberculosis (TB), could unlock and inform future TB research and treatment strategies.
TB remains one of the world's deadliest infectious diseases, yet the origins of M. Tuberculosis are still not fully understood.
In a new study published in PLOS Pathogens, research led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) details the newly identified bacterium, Mycobacterium spongiae, found in a marine sponge collected near Cooktown, Queensland.
Often referred to as 'chemical factories', marine sponges are a valuable source of bioactive compounds with potent anticancer, antibacterial, antiviral and anti-inflammatory properties. While studying a sponge specimen for its chemical-producing bacteria, researchers at the University of Queensland found a bacterium that puzzled them.
The sample was sent to the Doherty Institute, where the team conducted extensive analyses of the genes, proteins and lipids of M. Spongiae. They discovered that it shares 80 per cent of its genetic material with M. Tuberculosis, including some key genes associated with the bacteria's ability to cause disease. However, the researchers found that, unlike M. Tuberculosis, M. Spongiae does not cause disease in mice, making it non-virulent.
The University of Melbourne's Dr Sacha Pidot, a Laboratory Head at the Doherty Institute and co-lead author of the paper, said it was an exciting and important find.
"We were astounded to discover that this bacterium is a very close relative of M. Tuberculosis," said Dr Pidot.
"This finding provides new insights into the evolution of M. Tuberculosis, suggesting that these pathogens may have originated from marine mycobacteria."
The University of Melbourne's Professor Tim Stinear, a Laboratory Head at the Doherty Institute and co-lead author of the paper, said that that this new knowledge is an important building block for future research.
"While there is more work to be done in this space, this discovery is a valuable piece in the puzzle of understanding how TB came to be such a serious disease," said Professor Stinear.
"Our findings could help find weak links in M. Tuberculosis to inform the development of new strategies such as vaccines to prevent and combat tuberculosis."
Authors were from Bio21 Institute, University of Queensland, Institut Pasteur, UK Health Security Agency, University of Otago and WEHI.
Researchers Develop Four New Regimens To Treat People With Multidrug-resistant TB Meningitis
In a preliminary study with a small number of humans, rabbits and mice, researchers at Johns Hopkins Children's Center say they have developed four new regimens that have the potential to treat and save the lives of people with multidrug-resistant (MDR) tuberculous (TB) meningitis.
While TB meningitis -; which affects the brain and spine -; is extremely rare in the United States, worldwide it is believed to be the deadliest form of TB.
In a report that will be published Aug. 14 in Nature Communications, the investigators present the regimens, mainly composed of antibiotics already approved by the U.S. Food and Drug Administration (FDA) for other uses, or antibiotics currently in clinical trials. Study investigators say the regimens could be readily evaluated in new clinical studies, or used to treat people with MDR-TB meningitis on a case-by-case basis now.
According to the World Health Organization, tuberculosis remains a global public health threat, with the largest number of cases occurring in the Southeast Asian region and Africa, and is a leading killer by a single infectious agent, the tubercle bacillus. There are no FDA-approved antibiotic treatments specifically effective for tuberculous meningitis, although antibiotic treatments developed for TB of the lungs are widely available.
A previous Johns Hopkins Children's Center study led by Sanjay Jain, M.D., senior author of the new study and director of the Johns Hopkins Center for Infection and Inflammation Imaging Research, showed that the FDA-approved regimen of three antibiotics currently used for treating drug-resistant pulmonary TB -; bedaquiline, pretomanid and linezolid (BPaL) -; is not effective in treating TB meningitis, because bedaquiline and linezolid can't efficiently cross the blood-brain barrier -; a network of cells that prevents the entry of germs and toxins into the brain.
The new study used positron emission tomography (PET) scan and CT scan technology on people, rabbits and mice to show how different antibiotics penetrate the brain and other areas of the body, says Jain, who is also a pediatric infectious diseases specialist at Johns Hopkins Children's Center.
For the new experiments, researchers first created a chemically identical and scan-friendly version of the antibiotic pretomanid, and conducted a whole-body study in eight people: six healthy volunteers and two patients newly diagnosed with pulmonary TB. Using PET and CT imaging, researchers measured the antibiotic's penetration into the brain and lung tissue, and found that pretomanid penetrated the brain more than two times better than the lungs of all human subjects. Pretomanid levels in the cerebrospinal fluid (CSF) were also different from those in the brain.
We have found that CSF levels of antibiotics often have no relation to those in the brain."
Xueyi Chen, M.D., one of the study's first authors and pediatric infectious diseases fellow at the Johns Hopkins University School of Medicine
Next, using PET imaging, the researchers tested four different antibiotics (chemically identical and imageable versions) active against MDR-TB -; pretomanid, sutezolid, linezolid and bedaquiline -; and their penetration into the lung and brain tissues in mouse and rabbit models of TB meningitis.
All four antibiotics distributed well in the body, but with significantly different brain and lung tissue penetration. While pretomanid levels were significantly higher in the brain versus lung tissue, sutezolid, linezolid and bedaquiline had at least three times higher levels in lung tissue -; with bedaquiline demonstrating levels almost tenfold higher than in the brain. "Interestingly, pretomanid brain levels were double the amount in the plasma. In contrast, while bedaquiline brain levels were almost one-fifth the plasma levels, the lung levels were double the amount in the plasma. This preferential accumulation of different antibiotics in brain or lung tissues is very important, and explains why certain antibiotics are highly effective in the lungs, but not in the brain and vice versa," says Jain.
Researchers next created computer models that parallel and measure how drugs behave in living systems, so called pharmacokinetics, for pretomanid, sutezolid, linezolid and bedaquiline. Mathematical simulations based on the models were then used to predict which tissue exposures and doses would be necessary to attain therapeutic brain penetration of each antibiotic. Only pretomanid achieved therapeutic brain tissue exposures at the standard human oral dosing. Even at a dose four times the standard human oral dose, bedaquiline brain tissue exposures were predicted to be only one-third of the target levels.
Researchers found that the three pretomanid-based multidrug regimens -; BPa50LZ (bedaquiline, pretomanid, linezolid, pyrazinamide), Pa100LZ (pretomanid, linezolid, pyrazinamide), and Pa50LMxZ , (pretomanid, linezolid, moxifloxacin, pyrazinamide) -; were highly effective in treating TB meningitis in animal models when administered at human equivalent dosing. Each regimen's ability to kill bacteria in the brain was several magnitudes higher than both the standard TB treatment (R10HZ ) and the BPaL regimen (BPa50L ).
Since MDR-TB strains can also be resistant to pyrazinamide, researchers developed a fourth regimen, one without pyrazinamide: Pa100SMx (pretomanid, sutezolid, moxifloxacin). They found it was as effective as the first-line standard TB treatment, and 10 times better in reducing the bacterial burden in the brain than the BPaL regimen.
Investigators cautioned that their experiments were limited by the small quantities of the imageable version of antibiotics used per subject. However, several studies support that dosing with small quantities of a drug are a reliable predictor of a drug's bodily distribution.
Along with Jain and Chen, the study authors from Johns Hopkins include Oscar Nino-Meza, Mona Sarhan, Medha Byeonghoon Jeon, Elizabeth Tucker, Maunank Shah and Laurence Carroll. Other authors are Bhavatharini Arun and Vijay Ivaturi from the University of Maryland, Kishor Mane and Joel Freundlich from Rutgers University, and Charles Peloquin from University of Florida.
The study was funded by the U.S. National Institutes of Health R01-AI145435-A1, R01-AI153349, R01-HL131829, R21-AI149760, and K08-AI139371.
No Johns Hopkins University authors declared conflicts of interest under Johns Hopkins University School of Medicine policies.
Source:
Journal reference:
Chen, X., et al. (2024). Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs. Nature Communications. Doi.Org/10.1038/s41467-024-50989-4.
Brian May Responds To Backlash To Badger Cull Documentary
Last week, Brian May argued in his BBC2 documentary on bovine TB (bTB) and the badger cull that badgers were not the cause of reinfection of cow herds and the cull was unjustifiable. Now, the Agriculture and Horticulture Development Board (AHDB) will reportedly make a formal complaint to the BBC claiming that the documentary was biased and inaccurate.
Read more: Brian May Urges UK Government To End 'Hideous' Culling Of Badgers
In an earlier statement, AHDB said that Brian May: The Badgers, the Farmers and Me was "missing key evidence that would have helped to inform viewers on the facts about bovine TB."
It took four years to make the documentary, which followed the Queen guitarist and animal activist's efforts to understand the bTB crisis. Since 2013, a quarter of a million badgers have been slaughtered in a bid to stop the disease spreading to cows. Around 20,000 infected cows a year are also killed each year. Advocates of the badger cull say it has been effective, but critics say it isn't supported by the science.
On Wednesday, May responded to accusations of bias in the documentary. In an Instagram post, he explained why focusing on badgers for spreading bTB makes no sense. "There can be no bias in the programme because all 'sides' are represented in our team," he said, which included "one dairy farmer, one farm vet, one wildlife expert and myself, a curious and doggedly persistent scientist."
The documentary drew on 12 years of research into bTB and the cull at a farm in Devon, concluding that badgers are not the main route of disease transmission. Rather, it's poor biosecurity and the spreading of slurry (cow manure) on fields where cows end up grazing. Cows become infected through eating the pathogen that's found in the manure, according to the research. May also finds that government-provided tests for the disease are not very accurate, identifying only about half of infected cows.
Read more: AHDB Relaunches Meat And Dairy Campaign Despite Criticism From Doctors
AHDB claims that before the documentary aired that it "went to some effort to highlight to the BBC the importance of including peer reviewed evidence about how the disease is spread, the positive impact of badger culling on TB in cattle herds and the effectiveness of the current 25-year eradication strategy." It said that "this was not reflected in the final edit."
Farmers Weekly reports that the British Cattle Veterinary Association (BCVA), the Countryside Alliance, and NFU Cymru have also "expressed disappointment and concern over the documentary's portrayal of bovine TB and the badger cull."
In another article, Malcolm Bennett, a professor of zoonotic and emerging diseases at Nottingham University, told Farmers Weekly that the documentary is generally correct. It's "central argument that bovine TB is primarily a cattle disease that spreads largely within and between herds, sometimes over long distances through cattle movements, is generally agreed," he said.
A BBC spokesperson told Plant Based News that the documentary "features numerous voices in the debate on badger culling, including farmers and academics."
"It follows Sir Brian on his journey over a decade to understand the crisis caused by Bovine Tuberculosis and his opposition to the controversial badger cull," they added. "The BBC adheres to strict editorial guidelines on impartiality on this matter."
As an alternative to culling, regional Wildlife Trusts and volunteer groups run badger vaccination programmes. A cow vaccine has also been in the works for years but is still not ready for use. Keir Starmer's government has described the cull as "ineffective" and pledged to end it, but is still allowing existing cull licenses to continue.
Read more: Campaigners Call for An End To Meat Advertising In The UK
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