US researchers use AI to develop powerful new antibiotic

In a first, US researchers have used artificial intelligence to identify a powerful new antibiotic capable of killing several drug-resistant bacteria.

Antibiotics have been a cornerstone of modern medicine since the discovery of penicillin, but their effectiveness has seriously diminished in recent years as overuse has led to bacteria becoming resistant.

The scientists at MIT and Harvard trained a machine learning algorithm to analyze chemical compounds capable of fighting infections using different mechanisms than those of existing drugs.

Their findings were published in the journal Cell on Thursday.

"Our approach revealed this amazing molecule which is arguably one of the more powerful antibiotics that has been discovered," said James Collins, a professor of medical engineering at MIT and one of the paper's senior authors.

The team trained the model on about 2,500 molecules, identifying a compound they called "halicin" -- after the fictional artificial intelligence system from "2001: A Space Odyssey" -- for real world testing on strains of bacteria taken from patients and grown in lab dishes.

It was able to kill many bacteria that are resistant to treatment, including Clostridium difficile, Acinetobacter baumannii, and Mycobacterium tuberculosis.

It also cured two mice with A. baumannii, which has infected many US soldiers in Iraq and Afghanistan.

The strain of the infection in the mice was resistant to all known antibiotics, but a halicin ointment completely cured the mice within 24 hours.

The idea of using predictive computer models for discovery of drugs is not new, but had never been successful until now.

"The machine learning model can explore... large chemical spaces that can be prohibitively expensive for traditional experimental approaches," said Regina Barzilay, a professor of computer science at MIT.

The development raises hope for the future of antibiotics, and comes at a critical time: It is predicted that without immediate action to discover and develop new drugs, deaths attributable to resistant infections will reach 10 million a year by 2050.

The researchers plan to study halicin further and work with a pharmaceutical company or nonprofit to develop it for use in humans.

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Tuberculosis infection is temporary in most people

A recent study challenged the earlier belief that tuberculosis infection stays forever and that it could come back at any point and cause the disease again.

Based on a review of clinical studies, researchers show that people who test positive with immunologic TB skin or blood tests rarely develop TB. 

They suggest it’s because the infecting organism, Mycobacterium tuberculosis, is likely dead, wiped out naturally by people’s immune systems.

Despite that, these people retain an immunological memory to the disease, which the authors said likely explained why standard TB tests show a positive result since those tests look for an immune response and not live bacteria.

The findings upend commonly held beliefs, as well as approaches to care and research around the world, for the two billion people who test positive for TB and are thought to be persistently infected and at risk for active disease.

“The National Institutes of Health and other non-profit organisations spend millions of dollars on studies of the latent state because of the assumption that TB infection is life-long, held in check by the immune system,” said co-author of the study.

“However, based on our analysis, we believe that it is rarely life-long, and in 90 per cent or more of infected people, there is no possibility of TB development even with severe immunosuppression,” added another researcher.

In their review, the team pointed to several previous studies to demonstrate the natural history of TB immunoreactivity in people given preventive treatment, and of active TB in immunoreactive people with various forms of severe immunosuppression, like patients with HIV and those who have received an organ transplant.

“TB immunoreactivity is not a marker for the presence of continued TB infection,” a researcher wrote. “Rather, it serves as a sign of having been infected with TB at some point.”

The researchers believe future resources should focus on developing tests that can better identify infected people who are not symptomatic. Currently, there are no specific tests for these patients.

They also believe that detecting and treating people with active TB should be a high priority, as well as providing TB preventive therapy for those around them.

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New Tuberculosis drug may shorten treatment time for patients

A new experimental antibiotic for tuberculosis (TB) may be more effective than isoniazid, a decades-old drug which is currently one of the standard treatments for the disease, a study claims. In mouse models, the drug showed a much lower tendency to develop resistance, according to the study.

The drug remains in the tissues where the Mycobacterium tuberculosis bacteria reside for longer, killing them more effectively."The goal of TB drug development programmes is to develop universal treatment regimens that will shorten and simplify TB treatment in patients, which typically takes at least six months, and sometimes more than a year," said a researcher.

The new drug, called AN12855, has several advantages over isoniazid, which requires conversion to its active form by a Mycobacterial enzyme, KatG, in order to kill the pathogen. This creates a couple of problems. First, in some M tuberculosis, KatG is nonfunctional. That does not make M tuberculosis any less pathogenic, but it prevents the drug from working. That creates an easy avenue for the development of drug resistance, researchers said

Under selection pressure from isoniazid, the tuberculosis bacteria with nonfunctional KatG -- those that do not activate the drug -- are the ones that reproduce. Under these circumstances, drug resistance may develop. A hallmark of human tuberculosis is the presence of "heterogeneous pulmonary disease."

This includes a host defence involving confinement of invading bacteria within small cyst-like bodies called granulomas, that lack vasculature and often prevent the drug from reaching the pathogen. Most mouse TB models used for clinical evaluation of new drugs fail to produce this advanced lung pathology. Thus, they give little insight into how drugs might behave in the presence of advanced lung disease that is typical of human tuberculosis.

In the study, the researchers used a new TB mouse model that develops these M tuberculosis-containing granulomas to compare isoniazid and AN12855."We discovered that the drugs differed dramatically with respect to their abilities to kill the pathogen in highly diseased tissues. AN12855 proved more effective, without selecting for appreciable drug resistance," he said .

The superior efficacy is not surprising: AN12855 was superior in gaining entry and being retained in the granulomas, where M tuberculosis is found in highest numbers, he said."Whether this translates into improvements in the treatment of human disease will be the subject of future studies," he said.

"Our studies also further validate the use of a new TB mouse efficacy model (dubbed C3HeB/FeJ) as a research tool to study the impact of heightened human-like disease states on the activity and distribution of TB antibiotics that are in various stages of development," he said. That could accelerate the development of better TB treatments, researchers said. 

 

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Vitamin C increases effect of tuberculosis drugs

Suffering from tuberculosis? Include bell peppers, dark leafy greens, berries and oranges in your diet.
Studies in mice and in tissue cultures suggest that giving vitamin C with tuberculosis drugs could reduce the unusually long time it takes these drugs to eradicate this pathogen. 

In the study, the investigators treated Mycobacterium tuberculosis-infected mice with anti-tuberculosis drugs or vitamin C alone, or the drugs and vitamin C together. They measured M. tuberculosis (Mtb) organ burdens at four and six weeks post treatment.

Vitamin C had no activity by itself, but in two independent experiments, the combination of vitamin C with the first-line TB drugs, isoniazid and rifampicin, reduced the organ burdens faster than the two drugs without vitamin C, said the author. Experiments in infected tissue cultures demonstrated similar results, shortening the time to sterilization of the tissue culture by seven days.

"Our study shows that the addition of vitamin C to TB drug treatment potentiates the killing of Mtb and could shorten TB chemotherapy," said the principal investigator. That's important because treatment of drug susceptible tuberculosis takes six months, "resulting in some treatment mismanagement, potentially leading to the emergence and spread of drug-resistant TB," said the Dr.

Such long term treatment is needed for tuberculosis because a subpopulation of Mtb cells can form Mtb persister cells, dormant cells that are virtually impervious to antimicrobials.

In earlier studies, the investigators discovered that while high levels of vitamin C will kill actively dividing cells, lower concentrations will stimulate respiration and prevent the formation of persisters, said the Dr. Then, in the presence of TB drugs, that increased respiration will lead to rapid death of the cells. "Thus in our new paper, we postulate that vitamin C is stimulating respiration of the Mtb cells in mice, thus enabling the action of isoniazid and rifampicin."

A French study conducted in 1948 suggested that vitamin C was safe for humans, and potentially beneficial. Investigators gave high daily doses of vitamin C to terminally ill patients with no side effects. While the infection did not regress, that study characterized other effects as "remarkable:" bedridden patients regained appetite and physical activity.

Tuberculosis is a major worldwide public health problem, infecting the lungs and other organ systems. In 2016, the disease sickened more than 10 million people worldwide, and killed 1.7 million. In the United States, cases number in the low thousands, out of a population of around 3,30 million. Treatment of multidrug resistant TB takes at least two years, and requires use of toxic second-line TB drugs with severe side effects.

"Vitamin C is known to be safe and our current mouse studies suggest that vitamin C could enhance TB chemotherapy," said the Dr.. "A clinical trial of vitamin C with TB chemotherapies could demonstrate that such an adjunct therapy could reduce patients' exposure to toxic TB drugs and also reduce the spread of TB from infected individuals." 

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Gastric acid drug lansoprazole may also treat tuberculosis

Are you in the habit of consuming lansoprazole, a cheap and easily available gastric acid suppressant to cure heartburn, gastritis conditions and ulcers? Take heart, as such drugs can also keep you away from developing bacterial infections, especially tuberculosis. People who use lansoprazole to prevent conditions of acidity in the stomach are a third less likely to develop tuberculosis, a new study found. The study, stated that lansoprazole and similar drugs omeprazole or pantoprazole could work against the bacteria that causes tuberculosis, said to be one among the top ten infectious diseases that can even lead to death in severe cases.

“It would be a major breakthrough to find a new drug with useful activity against Mycobacterium tuberculosis and a favourable side effect profile — particularly a drug like lansoprazole, which costs pennies,” said a researcher.  “Laboratory, animal and now epidemiological data are all consistent with lansoprazole acting against the bacteria that cause tuberculosis. While it is too early to say whether lansoprazole can be used to treat tuberculosis, we think there is a strong case for further study.”

The researchers compared the people who take lansoprazole with those who consume omeprazole or pantoprazole just to check whether lansoprazole was more effective in killing Mycobacterium tuberculosis, while other drugs in the same class had no effect. The findings showed that among all the people using lansoprazole, there were 10 cases of tuberculosis per 100,000 person, compared to 15.3 cases among those using omeprazole or pantoprazole.

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Ancient herbal Chinese medicine can help fight TB

Researchers have found that centuries-old herbal medicine, discovered by Chinese scientists to treat malaria, can aid in tuberculosis (TB) treatment and even slow drug resistance.

One-third of the world's population is infected with TB, which killed 1.8 million people in 2015, according to the Centers for Disease Control and Prevention.

Mycobacterium tuberculosis (Mtb) -- the TB-causing bacteria -- needs oxygen to thrive in the body and the immune system starves this bacterium of oxygen to control the infection.

The study found that artemisinin -- the ancient remedy -- stopped the ability Mtb to become dormant -- a stage of the disease that often makes the use of antibiotics ineffective.

"When TB bacteria are dormant, they become highly tolerant to antibiotics. Blocking dormancy makes the TB bacteria more sensitive to these drugs and could shorten treatment times," said Robert Abramovitch, Assistant Professor at Michigan State University in the US.

Artemisinin attacks a molecule called heme, which is found in the Mtb oxygen sensor.

By disrupting this sensor and essentially turning it off, the medicine stopped the disease's ability to sense how much oxygen it was getting, the researchers said.

"When the Mtb is starved of oxygen, it goes into a dormant state, which protects it from the stress of low-oxygen environments. If Mtb can't sense low oxygen, then it can't become dormant and will die," Abramovitch said

TB takes up to six months to treat and is one of the main reasons the disease is so difficult to control, the researchers said.

They also said that the finding could be key to shortening the course of therapy because it can clear out the dormant, hard-to-kill bacteria.

The paper was published in the journal Nature Chemical Biology.

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Researchers have found that centuries-old herbal medicine, discovered by Chinese scientists to treat malaria, can aid in tuberculosis (TB) treatment and even slow drug resistance.

One-third of the world's population is infected with TB, which killed 1.8 million people in 2015, according to the Centers for Disease Control and Prevention.

Mycobacterium tuberculosis (Mtb) -- the TB-causing bacteria -- needs oxygen to thrive in the body and the immune system starves this ba ..

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