Improving nature’s own ability to kill dangerous bacteria

The Centers for Disease Control and Prevention considers antibiotic resistance one of the most urgent public health threats, one that affects communities worldwide. The ramifications of bacteria’s ability to become resistant to antibiotics can be seen in hospitals, public places, our food supply, and our water.

In their search for solutions, researchers at Rensselaer Polytechnic Institute have been looking to nature. In a paper recently published in Biomacromolecules, the team demonstrated how it could improve upon the ability of nature’s exquisitely selective collection of antimicrobial enzymes to attack bacteria in a way that’s much less likely to cause bacterial resistance.
“The idea is that we could take nature’s approach and just make it better,” said Jonathan Dordick, a chaired professor of chemical and biological engineering and a member of the Center for Biotechnology and Interdisciplinary Studies (CBIS), who led this research at Rensselaer with postdoctoral researcher Domyoung Kim and Senior Research Scientist Seok-Joon Kwon.
In order for bacteria to grow and live, they naturally produce autolysin enzymes that can break down their own cell walls, allowing those cells to divide and multiply.
In attacking one another, bacteria take advantage of a similar process, using an antibacterial protein known as a bacteriocin to kill a bacterium. Bacteria can also be attacked by bacteriophages, which are viruses that infect bacteria. They produce phage endolysin enzymes, which attack the bacterial cell from the inside. All three types of enzymes are broadly known as cell lytic enzymes, as they catalyze the breakdown of the bacterial cell wall.
“It’s very difficult for bacteria to become resistant to the action of these enzymes,” Dordick said. “For example, if they became resistant to an autolysin, they wouldn’t divide.”
Like building blocks, most cell lytic enzymes are modular. They’re made up of one binding domain which attaches to the cell wall, and a catalytic domain that breaks holes in the cell wall — effectively destroying the targeted bacteria.
These enzymes are very specific, Dordick said, targeting one or only a few bacteria. In this paper, the researchers set out to see if they could improve the combinations nature has created.
“The idea was: Could we use a Lego-like approach here? Could we take a binding domain from one enzyme and can we mix it with a binding domain or catalytic domain of another one?” Dordick said.
More specifically, the team took the protein streptavidin, which acts as an effective template to which the researchers could attach a binding domain from one organism and a catalytic domain from another. The modularity approach allows them to make new combinations quickly in order to determine which work best.
They found that in targeting Staphylococcus aureus — commonly known as staph — their combinations were very effective, at times even better than what occurs in nature.
“We genetically expressed the binding domains or the catalytic domains from several different organisms,” Dordick said. “We identified some that worked better than what nature provided. So that opens up an entirely new way of developing antimicrobial enzyme systems.”
“This research has the potential to improve human health,” said Deepak Vashishth, director of CBIS, a research center that brings faculty of multiple disciplines together to solve complex challenges. “It is emblematic of the innovative solutions that are needed to advance medical care.”
These findings lay the groundwork for further research and for improving the team’s creation of paints or coatings that could be applied to surfaces in order to seek out and kill targeted bacteria; to control and re-engineer various microbiomes found in nature; and potentially to be used clinically, for example, to control skin and intestinal infections.
This work was done in collaboration with a group led by Jungbae Kim, professor of chemical and biological engineering from Korea University. It was supported by a grant from the Global Research Laboratory Program through the National Research Foundation of Korea.

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Story Source:
Materials provided by Rensselaer Polytechnic Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Domyoung Kim, Seok-Joon Kwon, Jessica Sauve, Keith Fraser, Leighann Kemp, Inseon Lee, Jahyun Nam, Jungbae Kim, Jonathan S. Dordick. Modular Assembly of Unique Chimeric Lytic Enzymes on a Protein Scaffold Possessing Anti-Staphylococcal Activity. Biomacromolecules, 2019; DOI: 10.1021/acs.biomac.9b01134

https://www.sciencedaily.com/releases/2019/10/191010125624.htm

FDA guidance aims for loophole to avoid rebates

The FDA has completed a draft guidance that would create a legal loophole for drug companies to bypass legal commitments to pay rebates to PBMs and payers. The guidance, which is under review at the Office of Management and Budget, is intended to allow companies to sell drugs at net prices that don’t include rebate payments.

If and when it is implemented, HHS believes the guidance would enable drug companies to create a parallel market that would function alongside regular supply chains. In this separate channel, imported drugs could be sold at lower list prices to patients who are uninsured or who have large deductibles.

The guidance could also give companies the ability to free themselves from long-term contracts and negotiate new contracts for distributing drugs through conventional supply chains.

The scheme, first announced by HHS in a plan released in July, rests on FDA giving the green-light to a sleight of hand trick involving National Drug Codes (NDCs), codes that FDA assigns to drugs so it can track them throughout the supply chain.

Drug manufacturers would be permitted to obtain a new NDC for imported drugs.

While the imported products would be designated with different NDCs, manufacturers would be required to ensure that the imported drugs are identical to those produced for the U.S. market. The imported drugs would be manufactured in the same factories as those intended for the U.S. market.

Because contracts identify drugs by NDC, according to HHS, the manufacturers would be able to sell the imported drugs without regard to long-term contracts they had entered into for the U.S. market.

In its plan outlining the proposal, HHS said “multiple manufacturers have stated (either publicly or in statements to the Administration) that they wanted to offer lower cost versions but could not readily do so because they were locked into contracts with other parties in the supply chain. This pathway would highlight an opportunity for manufacturers to use importation to offer lower-cost versions of their drugs.”

The HHS plan downplayed safety concerns, stating that because drugs would “imported through conventional supply channels, this pathway generally would rely on applicable existing safeguards to ensure supply chain integrity.”

The proposal is, however, likely to raise safety concerns.

Beyond the potential for counterfeit or adulterated drugs entering the supply chain, there will be concerns that having identical products on the market with different NDCs could interfere with FDA’s ability to track drugs.

The scheme is also certain to face criticism — and possibly litigation — from PBMs and insurers who will argue that the government is inappropriately allowing drug manufacturers to slip out of legal commitments.

The FDA draft guidance on “Importation of Certain FDA-Approved Human Prescription Drugs, Including Biological Products” was sent Monday to the Office of Management and Budget for review. There is no deadline for OMB to complete the review.

https://www.biocentury.com/bc-extra/politics-policy/2019-10-08/fda-guidance-aims-loophole-avoid-rebates

Pain relief: When to use cold, when to use heat

Sore from a workout? You don’t have to reach for pain relief medicine when ice or heat will help. But when should you go cold and when should you go warm?

Ice is the go-to therapy when an injury first happens. It can stop the swelling of a sprained ankle, for instance, and numb the pain. The traditional approach is 20 minutes on, 20 minutes off at first. You might step this down to 20 minutes every two or three hours on the second and third days. If you have a long-term injury, icing the area for 10 to 20 minutes after a workout can be soothing.
Ice options include a plastic bag of crushed ice, a reusable ice pack or even a bag of peas that can be refrozen for use again—label it so no one eats them. Whatever you use, always place a thin towel between the ice and your skin to prevent skin damage.
Once the swelling of an injury is gone, you can switch to heat. Heat eases discomfort and promotes healing. With a chronic condition like arthritis, it can soothe achy joints and lessen your pain. You can follow the same type of schedule you would when icing.
Just as you don’t want to freeze your skin with ice, you don’t want to burn it with heat. So watch the settings on a heating pad. You want warmth, but you don’t want it to feel hot. Another choice is a reusable heat pack that you warm in the microwave. You can find versions that come shaped for the body part needing treatment. Even just a warm shower or bath can help. The water should be between the high 90s and 100 degrees.
Although these are considered safe at-home remedies, talk to your doctor first if your injury could be serious—for instance, you notice a lot of swelling and pain—or if you have any chronic health conditions, including any that prevent you from feeling hot and cold, like neuropathy, often from diabetes.
https://medicalxpress.com/news/2019-10-pain-relief-cold.html

Rotavirus infection may turn on type 1 diabetes

Rotavirus infection may play a role in the development of type 1 diabetes, according to a front matter article published October 10 in the open-access journal PLOS Pathogens by Leonard C. Harrison of the University of Melbourne in Australia, and colleagues.

Rotavirus remains the major cause of infantile gastroenteritis worldwide, although the advent of vaccination has substantially decreased associated mortality. Following the recent introduction of rotavirus vaccination, there has been a 15% decrease in the incidence of type 1 diabetes in Australian children under four years of age, suggesting that rotavirus vaccination could contribute to the primary prevention of this autoimmune disease. This finding complements human and animal studies implicating rotavirus in the development of type 1 diabetes in genetically susceptible children.
In the article, Harrison and colleagues begin by reviewing molecular evidence supporting their hypothesis and point out the association between rotavirus infection and serum islet autoantibodies. They also discuss results indicating that rotavirus infection induces pancreatic pathology, as well as environmental factors that promote the rise in incidence of type 1 diabetes. Finally, they review population-level data suggesting that rotavirus vaccination may be associated with a decrease in the incidence of type 1 diabetes. According to the authors, it will be important to identify which children are most likely to be protected by rotavirus vaccination. Moreover, future studies should aim to reveal disease mechanisms and directly demonstrate whether rotavirus infects the human pancreas prior to the onset of islet autoimmunity or type 1 diabetes.
Harrison concludes, “Vaccination against rotavirus may have the additional benefit in some children of being a primary prevention for type 1 diabetes.”

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Explore further

Possible link between rotavirus vaccine and decline in type 1 diabetes

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More information: Leonard C. Harrison et al, Does rotavirus turn on type 1 diabetes?, PLOS Pathogens (2019). DOI: 10.1371/journal.ppat.1007965

https://medicalxpress.com/news/2019-10-rotavirus-infection-diabetes.html

More Research Links Immune Cells to Alzheimer’s Disease

Increasingly, as the primary focus of Alzheimer’s research moves away from the beta-amyloid theory, it is shifting towards the role of immune cells in the brain called microglia.
Researchers at Washington University School of Medicine in St. Louis have found further evidence that microglia are the key link between the accumulation of abnormal proteins, like beta-amyloid and tau, in the brain and the actual brain damage observed in Alzheimer’s patients. They published their research in the Journal of Experimental Medicine.
The researchers noted that it was well known that chronic activation of the brain’s innate immune system is a well-known feature of Alzheimer’s and other primary tauopathies. But the extent to which that innate immune reaction contributes to neurodegeneration compared to the protein-induced neurotoxicity wasn’t clear. Their research showed that damage as the result of microglia’s activity, rather than the toxicity caused by tau accumulation, is the leading component driving neurodegeneration, at least in a mouse model.
“Right now many people are trying to develop new therapies for Alzheimer’s disease, because the ones we have are simply not effective,” said David Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, as well as senior author of the study. “If we could find a drug that specifically deactivates the microglia just at the beginning of the neurodegeneration phase of the disease, it would absolutely be worth evaluating in people.”
Under normal situations, tau is involved in normal, healthy brain neuron function. When it clumps into tangles in the brain, it is a mark of neurodegenerative diseases like Alzheimer’s and chronic traumatic encephalopathy, which has recently been linked to brain trauma seen in football players and boxers.
The researchers felt that there was more going on with microglia than just attempting to limit tau. Research has shown that once tau tangles form, microglia can harm the neurons close by, which contributes to neurodegeneration. There is also significant inflammation that can cause damage during this process.
Holtzman and first author, postdoctoral research Yang Shi, genetically modified mice that have a mutant form of human tau. These mice typically begin developing tau tangles at about six months of age and show neurological damage by nine months.
They then focused on the gene APOE, which has been linked to Alzheimer’s disease. Individuals with the APOE4 variant are 12 times more likely to develop Alzheimer’s compared to people with other variants. The scientific team modified the mice to carry the human APOE4 variant or no APOE gene. APOE4 was previously shown to amplify the toxic effects of tau on neurons.
They then fed the mice a compound that depletes microglia in the brain. Other mice were fed a placebo. At nine-and-a-half months, the brains of mice with tau tangles and the high-risk genetic variant had significantly smaller brains as long as the microglia were present. But when the microglia were eliminated, the mouse brains were basically normal and healthy with less evidence of abnormal tau tangles, even with the EPOE4 variant.
“Microglia drive neurodegeneration, probably through inflammation-induced neuronal death,” Shi said. “But even if that’s the case, if you don’t have microglia, or you have microglia but they can’t be activated, harmful forms of tau do not progress to an advanced stage, and you don’t get neurological damage.”
This is completely consistent with other findings that it is not the proteins, amyloid or tau, that cause the actual damage, but the immune response and resultant inflammation, that cause the damage.
Unfortunately, the compound the researchers used on mice is not a good option for drug development because of side effects, but it could point the way for other drugs that have similar mechanisms without the adverse effects.
“If you could target microglia in some specific way and prevent them from causing damage, I think that would be a really important, strategic, novel way to develop a treatment,” Holtzman said.
https://www.biospace.com/article/more-research-links-immune-cells-to-alzheimer-s-disease/

Immunic completes enrollment in mid-stage study of MS candidate IMU-838

Immunic (NASDAQ:IMUX) announces the completion of enrollment of 210 subjects in a Phase 2 clinical trial, EMPhASIS, evaluating lead candidate IMU-838 in patients with relapsing-remitting multiple sclerosis (RRMS).

The primary endpoint is the cumulative number of combined unique active MRI lesions at week 24 compared to placebo. The estimated primary completion date is November 2020.

The company says IMU-838 is an orally available, next-generation immune modulator that dampens the immune response by inhibiting an enzyme called dihydroorotate dehydrogenase (DHODH) that plays a key role in intracellular metabolism of activated immune cells.

https://seekingalpha.com/news/3505144-immunic-completes-enrollment-mid-stage-study-ms-candidate-imuminus-838

PhRMA CEO warns Pelosi bill to cut drug prices would be ‘devastating’ for industry

The head of the main pharmaceutical industry lobbying group on Thursday warned that a bill to lower drug prices from Speaker Nancy Pelosi (D-Calif.) would have a “devastating” effect on the industry and weaken its ability to develop new treatments.
The Pharmaceutical Research and Manufacturers of America (PhRMA) is one of the most powerful groups in Washington, and its CEO, Steve Ubl, outlined on Thursday the arguments the group is making as it seeks to ward off a push from the House, Senate and Trump administration to crack down on its prices.
“If H.R. 3 becomes law, it is lights out for a lot of very small biotech companies that are pre-revenue and depend on attracting capital,” Ubl told reporters on Thursday, using the formal name for Pelosi’s bill.Pelosi’s measure is expected to pass the House as soon as the end of October.
But the bill faces tough odds in the Republican-controlled Senate, where Senate Majority Leader Mitch McConnell (R-Ky.) has vowed to block what he has called “socialist price controls.”
Pelosi hopes if President Trump, who has long railed against high drug prices, endorses her bill, it would push it toward the finish line, though a potential deal could be more unlikely given the House’s impeachment inquiry against Trump.
Ubl, though, said his group is treating Pelosi’s measure, which would allow the government to negotiate lower prices on up to 250 drugs per year, as a real threat of becoming law, and is pushing back accordingly.
“I think there may be a mistaken notion in certain quarters that this is a messaging bill that won’t become law and therefore it’s a free vote, and we’re here to say otherwise,” Ubl told reporters. “This type of policy would have a devastating effect on the industry and the patients that we serve and we’re going to continue to take it very seriously and engage with policymakers accordingly.”
Supporters of the measure say the industry’s arguments that cutting drug prices would reduce innovation in new drugs is always the argument that industry makes to protect their high prices.
“It’s not going to hurt innovation,” Pelosi said at an event earlier this week in Washington state, saying that the bill would invest in research at the National Institutes of Health.
“We will have savings that we can reinvest in innovation that benefits everyone and not just the bottom line of the pharmaceutical industry,” she said.
House Democratic lawmakers were given a memo last month from focus groups of swing voters conducted by the firm Hart Research Associates. “Pharmaceutical companies’ claims that this bill will stifle investment in R&D are met with skepticism and have a very limited impact on swing voters,” the memo states. “Many see pharma’s message point as a scare tactic that drug companies have used for years to avoid reforms that will cut into their profits.”
Many leading drug companies are highly profitable. PhRMA argued on Thursday that reducing its companies’ profits would reduce the incentive for investors to take a risk by investing in drug companies, whose new treatments often fail somewhere along the line in development.
“We rely on capital investment to develop our R&D to produce new medicines,” said Lori Reilly, chief operating officer for PhRMA. “If you do diminish the return element, or the profitability element of that, you take away the incentive for many investors to put money in here, because there’s lots of places you can invest in, lots of places that carry a lot less risk.”
Sens. Chuck Grassley (R-Iowa) and Ron Wyden (D-Ore.) have proposed a somewhat more modest drug pricing bill.
But PhRMA also opposes that measure, and many doubt McConnell will bring up even that more modest bill.
Ubl argued that his group is not opposed to all action on drug prices, though, and would support actions that lower what patients pay out of pocket, rather than cutting the overall sticker price of the drug.
“The industry would support a balanced package,” he said. “We’re not for the status quo.”
https://thehill.com/policy/healthcare/465257-phrma-ceo-warns-pelosi-bill-to-lower-drug-prices-would-be-devastating-for