Posts Tagged ‘medicine’

Doctors have newly outlined a type of dementia that could be more common than Alzheimer’s among the oldest adults, according to a report published Tuesday in the journal Brain.

The disease, called LATE, may often mirror the symptoms of Alzheimer’s disease, though it affects the brain differently and develops more slowly than Alzheimer’s. Doctors say the two are frequently found together, and in those cases may lead to a steeper cognitive decline than either by itself.

In developing its report, the international team of authors is hoping to spur research — and, perhaps one day, treatments — for a disease that tends to affect people over 80 and “has an expanding but under-recognized impact on public health,” according to the paper.

“We’re really overhauling the concept of what dementia is,” said lead author Dr. Peter Nelson, director of neuropathology at the University of Kentucky Medical Center.

Still, the disease itself didn’t come out of the blue. The evidence has been building for years, including reports of patients who didn’t quite fit the mold for known types of dementia such as Alzheimer’s.

“There isn’t going to be one single disease that is causing all forms of dementia,” said Sandra Weintraub, a professor of psychiatry, behavioral sciences and neurology at Northwestern University Feinberg School of Medicine. She was not involved in the new paper.

Weintraub said researchers have been well aware of the “heterogeneity of dementia,” but figuring out precisely why each type can look so different has been a challenge. Why do some people lose memory first, while others lose language or have personality changes? Why do some develop dementia earlier in life, while others develop it later?

Experts say this heterogeneity has complicated dementia research, including Alzheimer’s, because it hasn’t always been clear what the root cause was — and thus, if doctors were treating the right thing.

What is it?

The acronym LATE stands for limbic-predominant age-related TDP-43 encephalopathy. The full name refers to the area in the brain most likely to be affected, as well as the protein at the center of it all.

“These age-related dementia diseases are frequently associated with proteinaceous glop,” Nelson said. “But different proteins can contribute to the glop.”

In Alzheimer’s, you’ll find one set of glops. In Lewy body dementia, another glop.

And in LATE, the glop is a protein called TDP-43. Doctors aren’t sure why the protein is found in a modified, misfolded form in a disease like LATE.

“TDP-43 likes certain parts of the brain that the Alzheimer’s pathology is less enamored of,” explained Weintraub, who is also a member of Northwestern’s Mesulam Center for Cognitive Neurology and Alzheimer’s Disease.

“This is an area that’s going to be really huge in the future. What are the individual vulnerabilities that cause the proteins to go to particular regions of the brain?” she said. “It’s not just what the protein abnormality is, but where it is.”

More than a decade ago, doctors first linked the TDP protein to amyotrophic lateral sclerosis, otherwise known as ALS or Lou Gehrig’s disease. It was also linked to another type of dementia, called frontotemporal lobar degeneration.

LATE “is a disease that’s 100 times more common than either of those, and nobody knows about it,” said Nelson.

The new paper estimates, based on autopsy studies, that between 20 and 50% of people over 80 will have brain changes associated with LATE. And that prevalence increases with age.

Experts say nailing down these numbers — as well as finding better ways to detect and research the disease — is what they hope comes out of consensus statements like the new paper, which gives scientists a common language to discuss it, according to Nelson.

“People have, in their own separate bailiwicks, found different parts of the elephant,” he said. “But this is the first place where everybody gets together and says, ‘This is the whole elephant.’ ”

What this could mean for Alzheimer’s

The new guidelines could have an impact on Alzheimer’s research, as well. For one, experts say some high-profile drug trials may have suffered as a result of some patients having unidentified LATE — and thus not responding to treatment.

In fact, Nelson’s colleagues recently saw that firsthand: a patient, now deceased, who was part of an Alzheimer’s drug trial but developed dementia anyway.

“So, the clinical trial was a failure for Alzheimer’s disease,” Nelson said, “but it turns out he didn’t have Alzheimer’s disease. He had LATE.”

Nina Silverberg, director of the Alzheimer’s Disease Research Centers Program at the National Institute on Aging, said she suspects examples like this are not the majority — in part because people in clinical trials tend to be on the younger end of the spectrum.

“I’m sure it plays some part, but maybe not as much as one might think at first,” said Silverberg, who co-chaired the working group that led to the new paper.

Advances in testing had already shown that some patients in these trials lacked “the telltale signs of Alzheimer’s,” she said.

In some cases, perhaps it was LATE — “and it’s certainly possible that there are other, as yet undiscovered, pathologies that people may have,” she added.

“We could go back and screen all the people that had failed their Alzheimer’s disease therapies,” Nelson said. “But what we really need to do is go forward and try to get these people out of the Alzheimer’s clinical trials — and instead get them into their own clinical trials.”

Silverberg describes the new paper as “a roadmap” for research that could change as we come to discover more about the disease. And researchers can’t do it without a large, diverse group of patients, she added.

“It’s probably going to take years and research participants to help us understand all of that,” she said.

https://www.cnn.com/2019/04/30/health/dementia-late-alzheimers-study/index.html

Advertisements

Williams Syndrome, a rare neurodevelopmental disorder that affects about one in 10,000 babies born in the United States, produces a range of symptoms including cognitive impairments, cardiovascular problems, and extreme friendliness, or hypersociability.

In a study of mice, MIT neuroscientists have garnered new insight into the molecular mechanisms that underlie this hypersociability. They found that loss of one of the genes linked to Williams Syndrome leads to a thinning of the fatty layer that insulates neurons and helps them conduct electrical signals in the brain.

The researchers also showed that they could reverse the symptoms by boosting production of this coating, known as myelin. This is significant, because while Williams Syndrome is rare, many other neurodevelopmental disorders and neurological conditions have been linked to myelination deficits, says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research.

“The importance is not only for Williams Syndrome,” says Feng, who is one of the senior authors of the study. “In other neurodevelopmental disorders, especially in some of the autism spectrum disorders, this could be potentially a new direction to look into, not only the pathology but also potential treatments.”

Zhigang He, a professor of neurology and ophthalmology at Harvard Medical School, is also a senior author of the paper, which appears in the April 22 issue of Nature Neuroscience. Former MIT postdoc Boaz Barak, currently a principal investigator at Tel Aviv University in Israel, is the lead author and a senior author of the paper.

Impaired myelination

Williams Syndrome, which is caused by the loss of one of the two copies of a segment of chromosome 7, can produce learning impairments, especially for tasks that require visual and motor skills, such as solving a jigsaw puzzle. Some people with the disorder also exhibit poor concentration and hyperactivity, and they are more likely to experience phobias.

In this study, the researchers decided to focus on one of the 25 genes in that segment, known as Gtf2i. Based on studies of patients with a smaller subset of the genes deleted, scientists have linked the Gtf2i gene to the hypersociability seen in Williams Syndrome.

Working with a mouse model, the researchers devised a way to knock out the gene specifically from excitatory neurons in the forebrain, which includes the cortex, the hippocampus, and the amygdala (a region important for processing emotions). They found that these mice did show increased levels of social behavior, measured by how much time they spent interacting with other mice. The mice also showed deficits in fine motor skills and increased nonsocial related anxiety, which are also symptoms of Williams Syndrome.

Next, the researchers sequenced the messenger RNA from the cortex of the mice to see which genes were affected by loss of Gtf2i. Gtf2i encodes a transcription factor, so it controls the expression of many other genes. The researchers found that about 70 percent of the genes with significantly reduced expression levels were involved in the process of myelination.

“Myelin is the insulation layer that wraps the axons that extend from the cell bodies of neurons,” Barak says. “When they don’t have the right properties, it will lead to faster or slower electrical signal transduction, which affects the synchronicity of brain activity.”

Further studies revealed that the mice had only about half the normal number of mature oligodendrocytes—the brain cells that produce myelin. However, the number of oligodendrocyte precursor cells was normal, so the researchers suspect that the maturation and differentiation processes of these cells are somehow impaired when Gtf2i is missing in the neurons.

This was surprising because Gtf2i was not knocked out in oligodendrocytes or their precursors. Thus, knocking out the gene in neurons may somehow influence the maturation process of oligodendrocytes, the researchers suggest. It is still unknown how this interaction might work.

“That’s a question we are interested in, but we don’t know whether it’s a secreted factor, or another kind of signal or activity,” Feng says.

In addition, the researchers found that the myelin surrounding axons of the forebrain was significantly thinner than in normal mice. Furthermore, electrical signals were smaller, and took more time to cross the brain in mice with Gtf2i missing.

Symptom reversal

It remains to be discovered precisely how this reduction in myelination leads to hypersociability. The researchers suspect that the lack of myelin affects brain circuits that normally inhibit social behaviors, making the mice more eager to interact with others.

“That’s probably the explanation, but exactly which circuits and how does it work, we still don’t know,” Feng says.

The researchers also found that they could reverse the symptoms by treating the mice with drugs that improve myelination. One of these drugs, an FDA-approved antihistamine called clemastine fumarate, is now in clinical trials to treat multiple sclerosis, which affects myelination of neurons in the brain and spinal cord. The researchers believe it would be worthwhile to test these drugs in Williams Syndrome patients because they found thinner myelin and reduced numbers of mature oligodendrocytes in brain samples from human subjects who had Williams Syndrome, compared to typical human brain samples.

“Mice are not humans, but the pathology is similar in this case, which means this could be translatable,” Feng says. “It could be that in these patients, if you improve their myelination early on, it could at least improve some of the conditions. That’s our hope.”

Such drugs would likely help mainly the social and fine-motor issues caused by Williams Syndrome, not the symptoms that are produced by deletion of other genes, the researchers say. They may also help treat other disorders, such as autism spectrum disorders, in which myelination is impaired in some cases, Feng says.

“We think this can be expanded into autism and other neurodevelopmental disorders. For these conditions, improved myelination may be a major factor in treatment,” he says. “We are now checking other animal models of neurodevelopmental disorders to see whether they have myelination defects, and whether improved myelination can improve some of the pathology of the defects.”

More information: Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug, Nature Neuroscience (2019). DOI: 10.1038/s41593-019-0380-9 , https://www.nature.com/articles/s41593-019-0380-9

https://medicalxpress.com/news/2019-04-neuroscientists-reverse-behavioral-symptoms-williams.html

Beauty might only be skin deep, but for those wondering how to keep that skin young, scientists may have found an answer in the form of a protein that encourages cell competition.

The prosaically named COL17A1 might not sound like a fountain of youth, but the new study suggests it does the heavy lifting when it comes to keeping skin intact and unimpaired.

The protein works by encouraging cell competition, a key process to maintain tissue fitness. That effectively “drives out” weaker cells while encouraging replication of stronger ones.

“Damaged or stressed stem cells can be selectively eliminated by intact stem cells every day in our skin,” said Emi Nishimura, a professor at the Tokyo Medical and Dental University’s Stem Cell Biology department, who led the research.

But ageing results in a depletion of COL17A1, as do familiar enemies of youthful skin, like UV radiation and other stress factors.

And when that happens, weaker cells replicate, leaving the skin thinner, more prone to damage and slower to heal.

The research published Thursday in the journal Nature is based on investigations using mice tails, which share many of the same characteristics as human skin.

After confirming the importance of COL17A1, the team decided to investigate whether they could stimulate the protein once it was depleted—effectively looking for compounds that could kickstart the anti-ageing process in skin.

They isolated two chemical compounds—Y27632 and apocynin—and tested both on skin cells, with positive results.

“Application of these drugs to full-thickness skin wounds significantly promoted wound repair,” the study said.

The two compounds point to ways of “facilitating skin regeneration and reducing skin ageing,” the study added.

In a review of the study commissioned by Nature, two professors from the University of Colorado said cell competition had previously only been studied extensively in fruit flies.

The research “provides evidence that healthy cells in mammals can also efficiently repopulate adult tissues, replacing unfit or damaged cells,” wrote professors Ganna Bilousova and James DeGregori.

And they said the research offered “proof-of-principle” that the two chemical compounds could combat ageing.

“Future studies are needed to determine the mechanisms of cell competition in other tissues, and to identify compounds capable of reversing ageing in other organs,” they said.

Nishimura told AFP that the work could eventually lead to products like creams or tablets that could stop skin deterioration and promote repair.

“We are going to collaborate with pharmaceutical or cosmetic companies for the clinical use of the chemicals,” she said.

She said additional research would investigate whether the same process might also be at work in other parts of the body that have so-called epithelial cells like skin does.

“We are working on other epithelial organs as well to find out (whether) similar competition may underlie long-term tissue maintenance as well as organ ageing,” she said.

https://medicalxpress.com/news/2019-04-young-uncovers-protein-skin-youthful.html

by CARLY CASSELLA

Scientists are closing in on a blood test for fibromyalgia, and the result could save patients from what is currently a lengthy and vague process of diagnosis.

Researchers at Ohio State University are now aiming to have a diagnostic blood test available for widespread use within the next five years.

Their confidence stems from a recently discovered biomarker – a “metabolic fingerprint” as the researchers put it – traceable in the blood of those with the disorder.

“We found clear, reproducible metabolic patterns in the blood of dozens of patients with fibromyalgia,” says lead author Kevin Hackshaw, a rheumatologist at Ohio State University.

“This brings us much closer to a blood test than we have ever been.”

Fibromyalgia is a common, debilitating, and poorly understood disorder, marked by widespread pain and fatigue, with no known cause and absolutely no cure.

In the United States, it’s the most common cause of chronic widespread pain, and that’s not even counting the thousands of patients who go undiagnosed every year.

Without a reliable way to detect this disorder, it’s estimated that up to three out of four people with the condition remain undiagnosed. And on average it can take five years from when a person’s symptoms first appear to them actually receiving a diagnosis.

In total, the US Centers for Disease Control and Prevention estimates that about two percent of the population – around four million adults – have fibromyalgia, with women making up a disproportionate slice.

Left with few options, many patients are simply forced to live with their pain.With nowhere to go, many become desperate and turn to potentially harmful treatments.

“When you look at chronic pain clinics, about 40 percent of patients on opioids meet the diagnostic criteria for fibromyalgia,” says Hackshaw.

“Fibromyalgia often gets worse, and certainly doesn’t get better, with opioids.”

It was Hackshaw’s goal to intervene sooner. Using vibrational spectroscopy, a technique which measures the energy of molecules, his team analysed blood samples from 50 people with fibromyalgia, 29 with rheumatoid arthritis, 19 with osteoarthritis, and 23 with lupus.

Despite the fact these disorders can present with similar symptoms, the blood of those participants with fibromyalgia was distinct.

Using these unique patterns, the researchers then tried to blindly predict participants’ diagnoses. Even without knowing their true disorder, the researchers were able to accurately diagnose every study participant based on that molecular fingerprint in the blood.

“These initial results are remarkable,” says co-author Luis Rodriguez-Saona, an expert in vibrational spectroscopy at Ohio State University.

“If we can help speed diagnosis for these patients, their treatment will be better and they’ll likely have better outlooks. There’s nothing worse than being in a grey area where you don’t know what disease you have.”

While the sample size is undoubtedly small, the results are promising. If the team can replicate their results on a larger scale, with a couple hundred diverse participants, then a blood test in five years might not seem so far-fetched.

Not to mention what that would mean for treatment. If the researchers can prove they really have identified a biological fingerprint for fibromyalgia, this could give us new drug targets in the future.

“Thus,” the authors conclude, “our studies have great importance both from development of a reproducible biomarker as well as identifying potential new therapeutic targets for treatment.”

This study has been published in the Journal of Biological Chemistry.

https://www.sciencealert.com/scientists-have-devised-a-blood-test-that-can-accurately-diagnose-fibromyalgia

by George Dvorsky

Using brain-scanning technology, artificial intelligence, and speech synthesizers, scientists have converted brain patterns into intelligible verbal speech—an advance that could eventually give voice to those without.

It’s a shame Stephen Hawking isn’t alive to see this, as he may have gotten a real kick out of it. The new speech system, developed by researchers at the ​Neural Acoustic Processing Lab at Columbia University in New York City, is something the late physicist might have benefited from.

Hawking had amyotrophic lateral sclerosis (ALS), a motor neuron disease that took away his verbal speech, but he continued to communicate using a computer and a speech synthesizer. By using a cheek switch affixed to his glasses, Hawking was able to pre-select words on a computer, which were read out by a voice synthesizer. It was a bit tedious, but it allowed Hawking to produce around a dozen words per minute.

But imagine if Hawking didn’t have to manually select and trigger the words. Indeed, some individuals, whether they have ALS, locked-in syndrome, or are recovering from a stroke, may not have the motor skills required to control a computer, even by just a tweak of the cheek. Ideally, an artificial voice system would capture an individual’s thoughts directly to produce speech, eliminating the need to control a computer.

New research published today in Scientific Advances takes us an important step closer to that goal, but instead of capturing an individual’s internal thoughts to reconstruct speech, it uses the brain patterns produced while listening to speech.

To devise such a speech neuroprosthesis, neuroscientist Nima Mesgarani and his colleagues combined recent advances in deep learning with speech synthesis technologies. Their resulting brain-computer interface, though still rudimentary, captured brain patterns directly from the auditory cortex, which were then decoded by an AI-powered vocoder, or speech synthesizer, to produce intelligible speech. The speech was very robotic sounding, but nearly three in four listeners were able to discern the content. It’s an exciting advance—one that could eventually help people who have lost the capacity for speech.

To be clear, Mesgarani’s neuroprosthetic device isn’t translating an individual’s covert speech—that is, the thoughts in our heads, also called imagined speech—directly into words. Unfortunately, we’re not quite there yet in terms of the science. Instead, the system captured an individual’s distinctive cognitive responses as they listened to recordings of people speaking. A deep neural network was then able to decode, or translate, these patterns, allowing the system to reconstruct speech.

“This study continues a recent trend in applying deep learning techniques to decode neural signals,” Andrew Jackson, a professor of neural interfaces at Newcastle University who wasn’t involved in the new study, told Gizmodo. “In this case, the neural signals are recorded from the brain surface of humans during epilepsy surgery. The participants listen to different words and sentences which are read by actors. Neural networks are trained to learn the relationship between brain signals and sounds, and as a result can then reconstruct intelligible reproductions of the words/sentences based only on the brain signals.”

Epilepsy patients were chosen for the study because they often have to undergo brain surgery. Mesgarani, with the help of Ashesh Dinesh Mehta, a neurosurgeon at Northwell Health Physician Partners Neuroscience Institute and a co-author of the new study, recruited five volunteers for the experiment. The team used invasive electrocorticography (ECoG) to measure neural activity as the patients listened to continuous speech sounds. The patients listened, for example, to speakers reciting digits from zero to nine. Their brain patterns were then fed into the AI-enabled vocoder, resulting in the synthesized speech.

The results were very robotic-sounding, but fairly intelligible. In tests, listeners could correctly identify spoken digits around 75 percent of the time. They could even tell if the speaker was male or female. Not bad, and a result that even came as “a surprise” to Mesgaran, as he told Gizmodo in an email.

Recordings of the speech synthesizer can be found here (the researchers tested various techniques, but the best result came from the combination of deep neural networks with the vocoder).

The use of a voice synthesizer in this context, as opposed to a system that can match and recite pre-recorded words, was important to Mesgarani. As he explained to Gizmodo, there’s more to speech than just putting the right words together.

“Since the goal of this work is to restore speech communication in those who have lost the ability to talk, we aimed to learn the direct mapping from the brain signal to the speech sound itself,” he told Gizmodo. “It is possible to also decode phonemes [distinct units of sound] or words, however, speech has a lot more information than just the content—such as the speaker [with their distinct voice and style], intonation, emotional tone, and so on. Therefore, our goal in this particular paper has been to recover the sound itself.”

Looking ahead, Mesgarani would like to synthesize more complicated words and sentences, and collect brain signals of people who are simply thinking or imagining the act of speaking.

Jackson was impressed with the new study, but he said it’s still not clear if this approach will apply directly to brain-computer interfaces.

“In the paper, the decoded signals reflect actual words heard by the brain. To be useful, a communication device would have to decode words that are imagined by the user,” Jackson told Gizmodo. “Although there is often some overlap between brain areas involved in hearing, speaking, and imagining speech, we don’t yet know exactly how similar the associated brain signals will be.”

William Tatum, a neurologist at the Mayo Clinic who was also not involved in the new study, said the research is important in that it’s the first to use artificial intelligence to reconstruct speech from the brain waves involved in generating known acoustic stimuli. The significance is notable, “because it advances application of deep learning in the next generation of better designed speech-producing systems,” he told Gizmodo. That said, he felt the sample size of participants was too small, and that the use of data extracted directly from the human brain during surgery is not ideal.

Another limitation of the study is that the neural networks, in order for them do more than just reproduce words from zero to nine, would have to be trained on a large number of brain signals from each participant. The system is patient-specific, as we all produce different brain patterns when we listen to speech.

“It will be interesting in future to see how well decoders trained for one person generalize to other individuals,” said Jackson. “It’s a bit like early speech recognition systems that needed to be individually trained by the user, as opposed to today’s technology, such as Siri and Alexa, that can make sense of anyone’s voice, again using neural networks. Only time will tell whether these technologies could one day do the same for brain signals.”

No doubt, there’s still lots of work to do. But the new paper is an encouraging step toward the achievement of implantable speech neuroprosthetics.

https://gizmodo.com/neuroscientists-translate-brain-waves-into-recognizable-1832155006

https://www.nature.com/articles/s41598-018-37359-z

Levels of a protein called neurofilament light chain increase in the blood and spinal fluid of some Alzheimer’s patients 16 years before they develop symptoms, according to a study published January 21 in Nature Medicine.

The results suggest that neurofilament light chain (NfL), which is part of the cytoskeleton of neurons and has previously been tied to brain damage in mice, could serve as a biomarker to noninvasively track the progression of the disease. “This is something that would be easy to incorporate into a screening test in a neurology clinic,” coauthor Brian Gordon, an assistant professor of radiology at Washington University, says in a press release.

Gordon and his colleagues measured NfL in nearly 250 people carrying an Alzheimer’s-risk allele and more than 160 of their relatives who did not carry the variant. They found that those at risk of developing the disease had higher levels of the protein early on, and that NfL levels in both the blood and spinal fluid were on the rise well before the patients began to show signs of neurodegeneration, more than 16 years before disease onset.

Examining a subset of the patients more closely, the team saw that the rate of increase in NfL correlated with the shrinkage of a brain region called the precuneus, and patients whose NfL levels were rising rapidly tested worse on cognitive tests. “It is not necessarily the absolute levels which tell you your neurodegeneration is ongoing, it is the rate of change,” coauthor Mathias Jucker, a professor of cellular neurology at the German Center for Neurodegenerative Diseases in Tübingen, tells The Guardian.

The Alzheimer’s-linked mutation carried by patients examined in this study only affects about 1 percent of people who get the neurodegenerative disease, so the approach must be validated in a broader patient population, James Pickett, the head of research at the Alzheimer’s Society, tells The Guardian.

“We validated it in people with Alzheimer’s disease because we know their brains undergo lots of neurodegeneration, but this marker isn’t specific for Alzheimer’s,” Gordon says in the release. “I could see this being used in the clinic in a few years to identify signs of brain damage in individual patients.”

Meanwhile, a research team at Seoul National University in South Korea described another potential blood test for Alzheimer’s, focusing on the tau and amyloid proteins known to be associated with the disease. According to their study published today in Brain, blood levels of tau and amyloid correlate with how much tau has accumulated in the brain, as well as other markers of neurodegeneration such as hippocampal volume. “These results indicate that combination of plasma tau and amyloid-β1–42 levels might be potential biomarkers for predicting brain tau pathology and neurodegeneration,” the researchers write in their report.

https://www.the-scientist.com/news-opinion/protein-changes-detected-in-blood-years-before-alzheimers-onset-65347


Case Western Reserve researchers cure drug-resistant infections without antibiotics

Biochemists, microbiologists, drug discovery experts and infectious disease doctors have teamed up in a new study that shows antibiotics are not always necessary to cure sepsis in mice. Instead of killing causative bacteria with antibiotics, researchers treated infected mice with molecules that block toxin formation in bacteria. Every treated mouse survived. The breakthrough study, published in Scientific Reports, suggests infections in humans might be cured the same way.

The molecules cling to a toxin-making protein found across Gram-positive bacterial species, called AgrA, rendering it ineffective. Treating mice with the therapeutic molecules effectively cured infections caused by methicillin-resistant Staphylococcus aureus (MRSA). S. aureus is notorious for its ability to overcome even the most potent antibiotics. Its resistance arsenal is broad, limiting therapeutic options to treat infections.

In a mouse model of S. aureus sepsis, treatment with small molecules alone resulted in 100 percent survival, while 70 percent of untreated animals died. The small molecules were as effective in promoting survival as antibiotics currently used to treat S. aureus infections. The molecules also appear to give antibiotics a boost. Septic mice treated with a combination of the small molecules and antibiotics had 10x fewer bacteria in their bloodstream than mice treated with antibiotic alone.

“For relatively healthy patients, such as athletes suffering from a MRSA infection, these molecules may be enough to clear an infection,” said Menachem Shoham, associate professor of biochemistry at Case Western Reserve University School of Medicine and senior author on the study. “For immunocompromised patients, combination therapy with the molecules and a low-dose antibiotic may be in order. The antibiotic in the combination could be one to which the bacteria are resistant in monotherapy, because our small molecules enhance the activity of conventional antibiotics, such as penicillin.”

With support from the small molecules, previously obsolete antibiotics could reenter the clinic.

Said Shoham: “This could provide a partial solution to the looming, global threat of antibiotic resistance.”

If available, antibiotics kill most bacteria, but a small number of bacteria with natural resistance survive. Over time, antibiotic-resistant bacteria multiply and spread. By Centers for Disease Control and Prevention estimates, at least two million Americans get an antibiotic-resistant infection annually. For some infections, effective antibiotics are no longer available. Disarming bacteria of disease-causing toxins represents a promising alternative to dwindling antibiotics.

Eliminating toxins frees up the immune system to eliminate bacterial pathogens instead of antibiotics, said Shoham, who also is affiliated with Q2 Pharma, Ltd., Haifa, Israel. “Without the toxins the bacteria become harmless. And since they don’t need the toxins to survive, there is less pressure to develop resistance.”

The small molecules work against multiple bacterial species. The new study included preliminary experiments showing the molecules prevent three other bacterial species from killing immune cells.

“These results indicate broad-spectrum efficacy against Gram-positive pathogens,” wrote the authors.

Added Shoham: “We have proven efficacy not only against MRSA but also against Staphylococcus epidermidis, which is notorious for clogging catheters, Streptococcus pyogenes that causes strep throat, Streptococcus pneumoniae, and other pathogens.”

Shoham led the study in collaboration with colleagues from the departments of biochemistry and dermatology and the Center for RNA and Therapeutics at Case Western Reserve University. The researchers developed two small molecules, F12 and F19, both of which potentiate antibiotic efficacy in the mouse models. The researchers are now working to commercialize both potential drugs. Case Western Reserve University has issued a license to Q2Pharma, Ltd., a biopharmaceutical startup company in Israel, to perform additional preclinical studies and develop F12 and F19 for clinical trials. Their initial trials will focus on patients suffering from systemic multi-drug resistant infections.

This research was supported by a Transformational Award to Menachem Shoham by the Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee. Some in vitro studies were supported by NIH/NIAID Preclinical Services under contract numbers HHSN272201100012I and HHSN27200007.

Greenberg, M, et al. “Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens.” Scientific Reports. 2018 Oct 1;8(1):14578. doi: 10.1038/s41598-018-32829-w. PMID: 30275455.