Year: 2023

Categories : Cancer Cardiovascular DiseaseTags :

Some Antihypertensives might Boost the Effectiveness of Cancer Immunotherapy

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A study reported in the latest issue of Nature has shown that some molecules previously used to treat hypertension might also help the immune system to better target cancer cells. The researchers believe that these findings could eventually be applied to significantly improve the effectiveness and applicability of cancer immunotherapy.

“Immunotherapy today can effectively fight only 30% to 40% of cancers,” said Benoît Van den Eynde, at the Ludwig Institute for Cancer Research, co-director of the de Duve Institute and professor of Tumour Immunology at the University of Oxford. “Many cancers are resistant, largely because their T lymphocytes are not reactive enough. We discovered that drugs once used to treat hypertension could have a very interesting effect in combating these forms of immunotherapy-resistant cancers.”

T lymphocytes are active components in the immune system, recognising and destroying cells that appear foreign. Cancer cells, however, are not foreign and are therefore often not recognised and attacked by T lymphocytes. But about thirty years ago, Thierry Boon and his colleagues at the former Brussels Branch of the Ludwig Institute for Cancer Research at the de Duve Institute discovered specific markers on the surface of cancer cells – tumour antigens – that can be recognised by T cells that then destroy the cancerous cells.

This work paved the way for cancer immunotherapy, a treatment approach that helps T cells destroy cancerous cells. Thanks to T cells’ specificity and memory of tumour antigens, immunotherapy makes it possible to treat advanced cancers with some success. It is now used worldwide. However, such therapies are not equally effective in all patients or against all types of cancer.

In the current study, a team led by Jingjing Zhu in Van den Eynde’s laboratory shows that anti-hypertensive drug-molecules known as α2-adrenergic receptor (α2AR) agonists also influence the behaviour of macrophages. While doing that job, macrophages also alert T cells of any abnormalities they encounter, presenting suspicious antigens to the cells to trigger a possible immune response.

Zhu, Van den Eynde and colleagues discovered that alongside their known hypotensive and anaesthetic effects, α2AR agonists can also stimulate macrophages in their role as sentinels, making T cells more reactive and more effective at rejecting cancer cells. The effect extended, most notably, to cancer models that are resistant to standard immunotherapy. This suggests the new approach could boost the efficacy of clinical immunotherapy, even for the many types of cancer that are largely unresponsive to such interventions.

These findings also present a rationale for the development of new molecules that might be used in combination with immunotherapy to improve its efficacy.

“One could imagine using existing blood pressure-lowering drugs,” said Van den Eynde. “But that would be quite risky, owing to the undesired effects and the toxicity of these drugs at the necessary doses. Another approach would be to develop new molecules that would act in the same way on macrophages but would not have the unwanted toxic effects. We have already made significant progress in this direction.”

Source: Ludwig Cancer Research

Categories : Antibiotics Healthcare Politics and RegulationsTags :

SA one of Many Countries Failing to Combat Antimicrobial Resistance, International Review Finds

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Methicillin resistant Staphylococcus aureus (MRSA) bacteria, the bane of hospital infection control strategies. Image by CDC on Unsplash.

Governments around the world must do more to tackle the growing threat of antimicrobial-resistant infections, new research suggests – with South Africa falling quite short in the rankings.

The review, published in The Lancet Infectious Diseases, assessed national action plans developed by more than 100 countries to tackle the threat from antimicrobial resistance (AMR). It comprehensively graded international AMR efforts and national action plans and generate comparable quantitative results across countries and regions.

National action plans focus on designing policies to curb AMR and devising tools to implement the policies – but they do not adequately factor in monitoring and evaluation.

The new research, carried out by experts at the universities of Leeds, Edinburgh and Hamburg, is the first large-scale analysis of these plans. They were designed after encouragement from the World Health Organisation, which has declared AMR one of the top 10 public health threats facing humanity.

Lead author Jay Patel, undergraduate dental student in the University of Leeds’ School of Dentistry, said: “Our analysis showed that countries were highly focused on designing AMR policies, and thinking about what tools would be required to implement those, but they generally did not consider how they would monitor and evaluate the impact of those efforts.

“This suggests that the international response may be inadequate to meet the scale and severity of AMR. This is particularly concerning in low and middle-income countries, where action plan activities often lack sustainable funding – relying instead on funds from foreign donors and philanthropies.

“The available evidence also suggests that simply developing a national action plan may not necessarily mean a country is more prepared to respond to the threat of AMR.

“Our study shows that the global response to AMR, and preparedness for the predicted challenges of AMR, require improvement in all locations around the world.”

The research team says governments across the world must strengthen their responses to AMR.

In 2017, the World Health Organization encouraged member states to develop national action plans stipulating how countries would tackle AMR. More than 100 countries have produced action plans, with several being implemented – but there had been no global analysis of the contents of these plans.

The 114 action plans, which were created in 2020-21, were evaluated against 54 elements, such as education, stewardship, and accountability, and each awarded a score out of 100. A mean score out of 100 for each country’s plan was then taken from these results.

The findings

At 43 points for AMR governance, South Africa falls far short of the top score of 85, and rather closer to the lowest score of 29. Reproduced from The Lancet. Figure 2b, Patel et al., 2023. (Open Access)

Norway’s response was the highest scoring with 85, followed by the USA with 84 and the UK with 83. The lowest scoring countries were Ukraine and Sierra Leone with 29 points each, and Barbados and Micronesia with 28 points. With 43 points, South Africa trailed behind Brazil, Namibia, Rwanda and Egypt – and received 0 for research and development as well as the effectiveness of its monitoring and evaluation.

The study found that across all plans, there was a greater focus on policy design and implementation tools, but efforts to monitor and evaluate activities are generally poorly-considered.

Of all areas evaluated, accountability and feedback mechanisms were the joint-lowest scoring, followed by education.

Training and professional education across human health, veterinary, and agricultural sectors were insufficient in many countries, with several lacking a sustainable workforce strategy to deliver antimicrobial stewardship policies.

Countries scored well on participation, demonstrating a shared awareness that AMR can only be successfully addressed through engagement with multiple sectors spanning human, animal and environmental health. Infection prevention and control was frequently recognised as a critical objective.

Source: University of Leeds

Categories : Implants and Prostheses NeurologyTags : 2 Comments

‘Digital Bridging’ Enables Paraplegic Man to Walk Again

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Study participant Gert-Jan Oskam walking with the brain-spine interface. Credit: Swiss Federal Institute of Technology in Lausanne

A 40 year-old man, Gert-Jan Oskam, has regained the ability to walk independently after being paralysed from a spinal cord injury with the use of a new brain-spine interface. The ‘digital bridging’ technology, developed at the Swiss Federal Institute of Technology in Lausanne and described in Nature, consists of implants and a computer to translate brain signals of the intention to move into stimulations that move the legs accordingly..

This BSI system could be calibrated in minutes, and remained stable for one year, including use at home. The BSI enabled the participant to exert natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains.

In addition to the digital bridging, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.

The system consists of a pair cortical of sensors, each an array with 64 electrodes housed in 5cm-diameter titanium discs. These discs are implanted snugly in the skull to pick up brain activity. They transmit the data wirelessly to a personalised headset, which also provides power for the sensors. The headset then sends the data to a portable processing unit (which may be carried in a backpack). Using specialised software, it uses this brain signal data to generates real-time predictions of motor intentions. These decoded intentions are translated into stimulation commands and sent on to another implant, a paddle array of 16 electrodes implanted next to the spinal cord, delivering current to the targeted dorsal root entry zones.

Neurosurgical implantation procedure

Oskam had sustained an incomplete cervical (C5/C6) spinal cord injury during a biking accident 10 years previously. He had already participated in a neurological recovery programme, the STIMO trial, which had used neurostimulation to get him to the stage where he could walk with the aid of a front-wheel walker. The neurorehabilitation from the trial also enabled him to use his hip flexors and lift his legs against gravity, but recovery had plateaued for the three years prior to his participation in the present study.

For the BSI to function, the researchers needed to locate neural features related to the intention to move the legs. To pinpoint the cortical regions associated with the intention to move, they used CT scans and magnetoencephalography. Taking into account anatomical restraints, they then decided on the positions of the implants.

Under general anaesthesia, surgeons performed a bicoronal incision of the scalp to allow two circular-shaped craniotomies over the planned locations of the left and right hemispheres. They then replaced the bone flaps with the two implantable recording devices, before closing the scalp.

The paddle lead had already been emplaced over the dorsal root entry zones of the lumbar spinal cord during the STIMO clinical trial. Its optimal positioning was identified using high-resolution structural imaging of the spine, and its final position was decided during the surgery based on electrophysiological recordings. The implantable pulse generator was inserted subcutaneously in the abdomen. Oskam was able to return home 24 hours after each procedure.

Categories : COVID Mental HealthTags :

Long COVID’s Fatigue Impacts can be Worse than Some Cancers

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A new UK study has found that fatigue is the most significant symptom for long COVID patients, and can affect quality of life more than some cancers. The research, published in BMJ Open, examines the impact of long COVID on the lives of over 3750 patients who were referred to a long COVID clinic and used a digital app as part of their NHS treatment for the condition.

Patients were asked to complete questionnaires on the app about how long COVID was affecting them – considering the impact of long COVID on their day-to-day activities, levels of fatigue, depression, anxiety, breathlessness, brain fog, and their quality of life.

The researchers, from UCL and the University of Exeter, found that many long COVID patients were seriously ill and on average had fatigue scores worse or similar to people with cancer-related anaemia or severe kidney disease. Their health-related quality of life scores were also lower than those of people with advanced metastatic cancers, like stage IV lung cancer.

Overall, the team found that the impact of long COVID on the daily activities of patients was worse than that of stroke patients and was comparable to that of patients with Parkinson’s disease.

Dr Henry Goodfellow, who co-led the study alongside the late Professor Elizabeth Murray (both UCL Institute of Epidemiology & Health), said: “Up to around 17% of people who get COVID go on to develop long COVID *. However, the impact of the condition on patients’ day-to-day lives isn’t fully understood.

“Our results have found that long COVID can have a devastating effect on the lives of patients – with fatigue having the biggest impact on everything from social activities to work, chores and maintaining close relationships.”

Not only does long COVID negatively impact the lives of patients on an individual level, the researchers also believe that it could have a significant economic and social impact on the country.

In order to be referred to a long COVID clinic, a patient must have had symptoms in keeping with long COVID for at least 12 weeks after an acute infection.

Over 90% of long COVID patients using the app were of working age (18-65) and 51% said they had been unable to work for at least one day in the previous month, with 20% unable to work at all.

Meanwhile, 71% of patients were female. As working-age women make up a majority of the health and social care workforce, the impact of long COVID on their ability to function may add additional pressures to already stretched services.

Dr Goodfellow said: “We hope that a greater understanding of the symptoms and impact of long COVID in these patients will help the NHS and policymakers to target limited resources by adapting existing services and designing new ones to better meet the needs of patients with long COVID .”

Alongside fatigue, long COVID patients typically experience breathlessness, anxiety, depression and brain fog. This is the first study to report on the impact of the condition on day-to-day functioning and health-related quality of life in patients who have been referred for specialist rehabilitation in long COVID clinics across England.

Dr Goodfellow said: “Our findings show that fatigue should be an important focus for clinical care and the design of rehabilitation services.

“Post-COVID assessment services should consider focusing on assessing and treating fatigue to maximise the recovery and return to work for sufferers of long COVID .”

Source: University College London

Categories : AgeingTags :

Muscle Adiposity may Indicate Cognitive Decline in Aging

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New research reveals that the level of muscle adiposity (fat content) may indicate a person’s likelihood of experiencing cognitive decline as they age. In the study published in the Journal of the American Geriatrics Society, a five-year increase in fat stored in the thigh muscle was a risk factor for cognitive decline.

This risk was independent of total weight, other fat deposits, and muscle characteristics (such as muscle strength or mass) and also independent of traditional dementia risk factors.

Investigators assessed muscle fat in 1634 adults 69–79 years of age at years 1 and 6 and evaluated their cognitive function at years 1, 3, 5, 8, and 10. Increases in muscle adiposity from year 1 to year 6 were associated with faster and more cognitive decline over time. The findings were similar for Black and White men and women.

“Our data suggest that muscle adiposity plays a unique role in cognitive decline, distinct from that of other types of fat or other muscle characteristics,” said corresponding author Caterina Rosano, MD, MPH, of the University of Pittsburgh’s School of Public Health. “If that is the case, then the next step is to understand how muscle fat and the brain ‘talk’ to each other, and whether reducing muscle adiposity can also reduce dementia risk.”

Source: Wiley

Categories : AgeingTags :

Immunomodulator Keeps Subclinical Arthritis from Developing into Full-blown Form

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Photo by Towfiqu barbhuiya: https://www.pexels.com/photo/person-feeling-pain-in-the-knee-11349880/

In a 12-month trial involving patients with “preclinical” rheumatoid arthritis, treatment with the immunomodulator abatacept (Orencia) kept the condition from becoming clinical, according to findings presented at the European Alliance of Associations for Rheumatology (EULAR) annual meeting.

Rheumatologists have long sought to nip rheumatoid arthritis (RA) in the bud, with many studies supporting early aggressive treatment on RA diagnosis. This has never been recommended for biologic therapies however.

Nevertheless, some patients show up at arthritis clinics with a few painful joints and other features such as RA-related serum biomarkers that suggest progression to full-blown RA is likely. Would aggressive treatment help slow their decline into RA?

In a phase IIb randomised trial involving patients in the UK and Netherlands who were at high risk for developing RA, only seven of the 110 assigned to abatacept had gone on to develop clinical arthritis after 1 year, compared with 30 of 103 in a placebo group.

The effect waned after abatacept was stopped at the one-year mark, and in the following year, 20 more patients in the abatacept group developed clinical arthritis, as did another eight in the placebo group.

Though the abatacept regimen held the edge for a full two years, projections showed that it was likely that the abatacept group would catch up with additional follow-up. At the same time, abatacept had no particular safety issues and thus could likely be continued.

A decade ago, Andrew Cope, MD, MBBS, of King’s College London colleagues thought about aggressive prevention, registering the current trial, Arthritis Prevention in the Pre-clinical Phase of RA with Abatacept (APIPPRA), in 2014. In a 2019 description of the protocol, they explained the selection of abatacept because “it targets immune reactions early in the chain of events leading to inflammation in RA. It functions by interrupting the interaction between T cells and antigen-presenting cells, attenuating the co-stimulatory signals required for T-cell activation, differentiation and effector responses,” thereby resulting “in downstream immunomodulatory effects on other inflammatory cells of the immune system.”

Participants had to show joint pain but no synovitis, plus either test positive for anti-citrullinated protein antigen (ACPA) antibodies and for rheumatoid factor (RF), or show high levels of ACPA antibodies without RF. The primary endpoint was development of clinically apparent arthritis in at least three joints or diagnosis of RA according to standard criteria.

While the preventive effect seen in the primary analysis did not hold up across the whole sample, Cope noted that it appeared more so in one very-high-risk subgroup: 49 patients who had some level of IgG ACPA antibodies and who were also positive for a series of other biomarkers, including RF, IgA ACPA antibodies, anti-carbamylated protein antibodies, and anti-acetylated peptide antibodies. For this subgroup, only about 10% of those who had taken abatacept progressed to clinical arthritis after two years, versus 50% of those assigned to placebo.

Source: MedPage Today

Categories : Ageing Cardiovascular DiseaseTags :

Oestrogen Pills may Increase Hypertension Risk

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Women ages 45 years and older taking oral oestrogen pills were more likely to develop hypertension than those using transdermal or vaginal formulations, according to new research published in Hypertension.

Less oestrogen and progesterone is produced in a woman’s body after menopause, which may increase the risk for cardiovascular diseases including heart failure, according to the American Heart Association.

Hormone therapy may be prescribed to relieve symptoms of menopause, in gender-affirming care and in contraception. Previous studies have found that some hormone therapies may reduce cardiovascular disease risk in menopausal women under 60 years of age or for whom it has been fewer than 10 years since menopause. The authors of this study noted that while hypertension is a modifiable risk factor for cardiovascular disease, the potential effects of different types of hormone therapy on blood pressure in menopausal women remain uncertain. 

“We know oestrogens ingested orally are metabolised through the liver, and this is associated with an increase in factors that can lead to higher blood pressure,” said lead study author Cindy Kalenga, an MD/PhD-candidate at the University of Calgary. 

“We know that post-menopausal women have increased risk of high blood pressure when compared to pre-menopausal women, furthermore, previous studies have shown that specific types of hormone therapy have been associated with higher rates of heart disease,” Kalenga said. “We chose to dive deeper into factors associated with hormone therapy, such as the route of administration (oral vs non-oral) and type of oestrogen, and how they may affect blood pressure.”

This study involved a large group of over 112 000 women, ages 45 years and older, who filled at least two consecutive prescriptions (a six-month cycle) for oestrogen-only hormone therapy, as identified from health administrative data in Alberta, Canada between 2008 and 2019. The main outcome of high blood pressure (hypertension) was identified via health records.

First, researchers investigated the relationship between route of oestrogen-only hormone therapy administration and risk of developing high blood pressure at least one year after starting the treatment. The 3 different routes of hormone therapy administration were oral (by mouth), transdermal and vaginal application. Additionally, researchers evaluated the formulation of oestrogen used and the risk of developing high blood pressure. For this study, the researchers reviewed medical records of individuals taking oestrogen-only hormone therapy. The two most common forms of oestrogen used by study participants were oestradiol – a synthetic form of oestrogen closest to the naturally produced form – and conjugated equine oestrogen, an animal-derived form of oestrogen and the oldest type of oestrogen therapy.

The analysis found:

  • Women taking oral oestrogen therapy had a 14% higher risk of developing high blood pressure compared to those using transdermal oestrogen and a 19% higher risk of developing high blood pressure compared to those using vaginal oestrogen creams or suppositories. After accounting for age, a stronger association was seen among women younger than 70 years of age compared to women older than 70.
  • Compared to estradiol, conjugated equine estrogen was associated with an 8% increased risk of developing high blood pressure.

Taking oestrogen for a longer period of time or taking a higher dose was associated with greater risk of high blood pressure, the authors noted. According to Kalenga, the study’s findings suggest that if menopausal woman take hormone therapy, there are different types of oestrogen that may have lower cardiovascular risks.

“These may include low-dose, non-oral oestrogen – like oestradiol, in transdermal or vaginal forms – for the shortest possible time period, based on individual symptoms and the risk–benefit ratio, Kalenga said. “These may also be associated with the lowest risk of hypertension. Of course, this must be balanced with the important benefits of hormone therapy, which include treatment of common menopausal symptoms.”

The average age of natural menopause among women worldwide is about 50 years of age. Current evidence supports that initiating menopausal hormone therapy in the early stages may have cardiovascular benefits, though not in the late stages of menopause, according to the American Heart Association’s 2020 Statement on Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention. Previous studies have found that menopausal hormone therapy may help relieve symptoms of menopause, including hot flashes, night sweats, mood changes or sleep disturbances.

Limitations included being based only on medical records, not including women younger than the age of 45 and not collecting data about hysterectomies or menopausal status (which was inferred by taking oestrogen after 45).

The authors will be conducting more research investigating combined oestrogen and progestin, as well as progestin-only formulations of hormone therapy and their impact on heart and kidney diseases.

Source: American Heart Association

Categories : Ophthalmology Paediatrics

Atropine Eyedrops Shown to Slow Progression of Myopia in Children

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The first drug therapy to slow the progression of nearsightedness in children is a step closer after the results of a successful clinical trial.

The results of the CHAMP (Childhood Atropine for Myopia Progression) trial were published in JAMA Ophthalmology. The three-year study found that a daily drop in each eye of a low dose of atropine, a drug used to dilate pupils, was better than a placebo at limiting eyeglass prescription changes and inhibiting elongation of the eye in nearsighted children aged six to 10.

About one in three adults worldwide is nearsighted, and the global prevalence of myopia is predicted to increase to 50% by 2050. Though one federally approved contact lens can slow progression of nearsightedness, no pharmaceutical products are approved in the US or Europe to treat myopia.

That elongation of the eyeball leads to myopia which starts in young children and progresses into the teen years before levelling off in most people. In addition to requiring life-long vision correction, nearsightedness increases the risk for retinal detachment, macular degeneration, cataracts and glaucoma later in life – and most corrective lenses don’t do anything to stop myopia progression.

“The idea of keeping eyeballs smaller isn’t just so people’s glasses are thinner – it would also be so that in their 70s they don’t suffer visual impairment,” said lead study author Karla Zadnik, professor and dean of the College of Optometry at The Ohio State University.

“This is exciting work for the myopia research community, which I’ve been part of for 35 years. We’ve talked about treatment and control for decades,” she said. “And it’s exciting to think that there could be options in the future for millions of children we know are going to be myopic.”

Animal studies years ago hinted at atropine’s ability to slow the growth of the eye, but the full-strength drug’s interference with near vision and concerns about pupil dilation hindered early considerations of its potential as a human therapy for myopia. More recent research has suggested a low dose of atropine might be the ticket.

This new double-masked, randomised phase 3 trial assessed the safety and effectiveness of two low-dose solutions, with atropine concentrations of either .01% or .02%, versus placebo. Treatment for each of the 489 children ages six to 10 assessed for the drug’s effectiveness consisted of one daily drop per eye at bedtime, which minimised the disruption of any blurring effects atropine might have on vision.

Researchers were a bit surprised to find that the most significant improvements at all time points compared to placebo resulted from the solution containing .01% of atropine. Though the .02% atropine formulation was also better at slowing progression of myopia than placebo, the results were less consistent.

“The .01% story is clearer and more obvious in terms of significantly slowing both the growth of the eye as well as then resulting in a lower glasses prescription,” Zadnik said.

Including a measure of the eye’s growth was a key component of the study because “the field is actually moving toward axial elongation being as important as, or more important than, the glasses prescription in terms of the most meaningful outcome,” she said. “If we’re trying to slow eye growth to prevent bad outcomes for people in their 80s, measuring the eye growth directly is really important.”

The drugs’ safety was assessed in a larger sample of 573 participants that also included children as young as 3 and up to age 16. Both low-dose formulations were safe and well tolerated. The most common side effects were sensitivity to light, allergic conjunctivitis, eye irritation, dilated pupils and blurred vision, although reports of these side effects were few.

The CHAMP trial was the first study of low-dose atropine to include placebo controls for three years and to involve a large, diverse population recruited from 26 clinical sites in North America and five countries in Europe. In a second section of the trial, researchers are evaluating how the eyes respond when the treatment is over.

Source: Ohio State University

Categories : Metabolic DisordersTags :

Safety and Efficacy of Oral Semaglutide Shown in Clinical Trial Success

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Participants taking a daily 50mg dose of oral semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, lost more weight than those taking placebo, according to results announced by the manufacturer, Norvo Nordisk.

Novo Nordisk announced headline results from phase 3a trial in a statement. The OASIS 1 trial is a 68-week, efficacy and safety trial comparing once-daily oral semaglutide 50mg for weight management to placebo in 667 adults with obesity or overweight with one or more comorbidities. Participants also undertook lifestyle interventions.

When evaluating the effects of treatment if all people adhered to treatment from a mean baseline body weight of 105.4 kg, people treated with oral semaglutide 50mg achieved a statistically significant weight loss of 17.4% after 68 weeks compared to a 1.8% reduction with placebo. In addition, 89.2% of those who received oral semaglutide 50mg, reached a weight loss of 5% or more after 68 weeks, compared to 24.5% with placebo.

When applying the treatment policy estimand, people treated with oral semaglutide 50 mg achieved a superior weight loss of 15.1% compared to a reduction of 2.4% with placebo and 84.9% achieved a weight loss of 5% or more, compared to 25.8% with placebo.

“We are very pleased with the weight loss demonstrated by the once-daily oral formulation of semaglutide in obesity. The results show comparable weight loss as in the STEP 1 trial with injectable semaglutide 2.4mg in obesity branded as Wegovy®”, said Martin Holst Lange, executive vice president for Development at Novo Nordisk. ”The choice between a daily tablet or weekly injection for obesity has the potential to offer patients and healthcare providers the opportunity to choose what best suits individual treatment preferences”.

Oral semaglutide 50 mg also appeared be safe and was well tolerated, with the most common adverse events being mostly mild to moderate gastrointestinal ones consistent with the GLP-1 receptor agonist class. Gastrointestinal adverse events were most prominent during dose escalation.

Novo Nordisk expects to file for regulatory approval in the US and the EU in 2023. The global launch of oral semaglutide 50mg is contingent on portfolio prioritisations and manufacturing capacity.

Source: Novo Nordisk

Categories : Antibiotics New Compounds and TreatmentsTags :

Scientists Use Modified Peptides to Create New Class of Antibiotics

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New antibiotics are urgently needed to tackle resistant bacteria. Researchers at the University of Zurich and the company Spexis have now modified the chemical structure of naturally occurring peptides to develop antimicrobial molecules that bind to novel targets in the bacteria’s metabolism.

In a study recently published in Science Advances, chemist Oliver Zerbe, head of the NMR facilities at the University of Zurich now discusses the development of a highly effective class of antibiotics that fight Gram-negative bacteria in a novel way.

The WHO classifies this group of bacteria as extremely dangerous. The group, whose resistance is particularly high due to their double cell membrane, includes carbapenem-resistant enterobacteria, for example.

Natural peptide chemically optimised

The starting point for the researchers’ study was a naturally occurring peptide called thanatin, which insects use to fend off infections. Thanatin disrupts an important lipopolysaccharide transport bridge between the outer and inner membrane of Gram-negative bacteria, as revealed a few years ago in a study by now retired UZH professor John Robinson. As a result, these metabolites build up inside the cells, and the bacteria perish. However, thanatin isn’t suitable for use as an antibiotic drug, among other things due to its low effectiveness and because bacteria quickly become resistant to it.

The researchers therefore modified the chemical structure of thanatin to enhance the peptide’s characteristics. “To do this, structural analyses were essential,” says Zerbe. His team synthetically assembled the various components of the bacterial transport bridge and then used nuclear magnetic resonance (NMR) to visualize where and how thanatin binds to and disrupts the transport bridge. Using this information, researchers from Spexis AG planned the chemical modifications that were necessary to boost the peptide’s antibacterial effects. Further mutations were made to increase the molecule’s stability, among other things.

Effective, safe and immune to resistance

The synthetic peptides were then tested in mice with bacterial infections – and yielded outstanding results. “The novel antibiotics proved very effective, especially for treating lung infections,” says Zerbe. “They are also highly effective against carbapenem-resistant enterobacteria, where most other antibiotics fail.” In addition, the newly developed peptides aren’t toxic or harmful to the kidneys, and they also proved stable in the blood over a longer period – all of which are properties that are required for gaining approval as a drug. However, further preclinical studies are needed before the first tests in humans can begin.

When choosing the most promising peptides for their study, the researchers made sure that they would also be effective against bacteria that have already developed resistance to thanatin. “We’re confident this will significantly slow down the development of antibacterial resistance,” says Zerbe. “We now have the prospect of a new class of antibiotics becoming available that is also effective against resistant bacteria.”

Source: University of Zurich