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.”
Portable ultrasound devices could provide an alternative to x-ray machines for diagnosing forearm fractures in children, which could alleviate waiting times for families in hospital emergency departments (ED).
Griffith University researchers Professor Robert Ware and Senior Lecturer Peter Snelling compared functional outcomes in children given an ultrasound and those who received an x-ray on a suspected distal forearm fracture. Dr Snelling said the ultrasounds were performed by nurses, physiotherapists and emergency physicians at four south-east Queensland hospitals.
“They treated 270 children, aged between five and 15 years, during the randomised trial, which included a check-up 28 days later and another check-in at eight weeks,” Dr Snelling said. “The findings show the majority of children had similar recoveries and returned to full physical function.”
Less than one-third of children who were given an ultrasound needed a follow-up x-ray and care at an orthopaedic clinic. Those who didn’t have a buckle fracture or fractured arm were discharged from hospital without the need for further imaging.
Professor Ware said children who had an ultrasound initially had fewer x-rays, and shorter stays in the ED. “Families were also more satisfied with the treatment they received,” he said. “The results are promising and have wider implications beyond in hospital diagnosis and follow up care.
“By using a bedside ultrasound, this frees up the x-ray machine for patients who really need it and can potentially be a cost-cutting measure for hospitals as they reduce the number of x-rays without comprising the safety of patients.
“It also would be extremely beneficial in rural or remote areas eliminating the need for children and their families to travel to a larger hospital for an x-ray.”
In a study published in the New England Journal of Medicine, scientists report that a new targeted therapy drug can extend progression-free survival for a subtype of glioma. The finding suggests a possible new treatment option for people with the slow-growing but deadly brain tumour.
The team, co-led by UCLA, found the drug vorasidenib more than doubled progression-free survival in people with recurrent grade 2 glioma with IDH1 and IDH2 mutations. Compared with placebo, those who took vorasidenib went for nearly 17 more months without their cancer worsening, delaying the time before they needed to begin chemotherapy and radiation.
The type of glioma studied in the paper, recurrent grade 2 glioma with IDH1 and IDH2 mutations, tends to affect younger people, often those in their 30s. The current standard treatment, a combination of radiation and chemotherapy, can cause neurological deficits that make it hard for patients in an often challenging and busy stage of life.
UCLA professor of neuro-oncology Dr Timothy Cloughesy, co-senior author of the study, said that the availability of a treatment that enables patients to go for longer periods of time between chemotherapy and radiation treatments could have a major impact.
“We’re always concerned about the delayed effects of radiation,” said Cloughesy. “Having the ability to hold off on getting radiation therapy to the brain with an effective therapy is really critical and very meaningful to this population of patients.”
Vorasidenib is a dual inhibitor of mutant IDH1/2, meaning that it prevents the formation and accumulation of the onco-metabolite 2-Hydroxyglutarate, or 2-HG, that occurs when genetically altered versions of two enzymes, IDH1 and IDH2, are present in a tumour. 2-HG is thought to be responsible for the formation and maintenance of IDH-mutant gliomas.
The study is also the first clinical trial to analyse a targeted therapy drug specifically developed to treat brain cancer. Targeted therapies focus on specific molecules that are involved in cancer cell growth and metastasis. Unlike chemotherapy and other therapies that can affect both cancerous and healthy cells, targeted therapies only attack cancer cells with the mutated target while sparing normal cells.
While there has been great progress in using targeted therapies to treat many types of cancer, the difficulty of crossing the blood-brain barrier makes developing targeted therapies for brain tumours challenging. Vorasidenib is a brain-penetrant inhibitor, allowing it to cross the blood-brain barrier.
The study involved 331 people aged 12 and older who had been diagnosed with recurrent grade 2 glioma with the IDH1 and IDH2 mutations and who had undergone brain tumour surgery. From that group, 168 were randomised to vorasidenib and 163 to placebo.
Among those who received vorasidenib, the disease did not progress for an average of 27.7 months, significantly longer than the 11.1 months for those who received the placebo. And among those who received vorasidenib, 85.6% went for 18 months before their next treatment, while 83.4% went for 24 months between treatments.
The disease progressed in just 28% of people receiving v orasidenib, compared to 54% of those receiving placebos. And as of September 2022, which was 30 months after the study began, 72% of patients who were in the vorasidenib group were still taking the drug and their disease had not progressed.
For patients who were originally in the placebo group whose cancer began to progress during the study, doctors permitted a switch to vorasidenib. The researchers observed limited adverse side effects from vorasidenib. “This is the first targeted treatment that shows unequivocal efficacy in this population and is precedent-setting for this disease,” Cloughesy said.
A recent study published in JAMA Network Open suggests that relief might be possible for debilitating cases of tinnitus by using a bi-sensory approach, combining mild but bothersome electrical stimulation with sound.
The study, by researchers at the University of Michigan’s Kresge Hearing Research Institute, was based on research into the processing of bi-sensory information, which could be used for personalised stimulation to treat tinnitus.
In a double-blind, randomised clinical trial, researchers recruited 99 individuals with somatic tinnitus, which 70% of tinnitus sufferers have. In this form, movements such as clenching the jaw, or applying pressure to the forehead, cause a noticeable change in pitch or loudness of experienced sounds.
Susan Shore, PhD, Professor Emerita in Michigan Medicine’s Department of Otolaryngology and U-M’s Departments of Physiology and Biomedical Engineering, led the research, in which candidates with bothersome, somatic tinnitus, as well as normal-to-moderate hearing loss, were eligible to participate.
“After enrolment, participants received a portable device developed and manufactured by in2being, LLC, for in-home use,” she said. “The devices were programmed to present each participant’s personal tinnitus spectrum, which was combined with electrical stimulation to form a bi-sensory stimulus, while maintaining participant and study team blinding.”
Study participants were randomly assigned to one of two groups. The active group received bi-sensory treatment first, while the control group received sound-only treatment first.
For the first six weeks, participants were instructed to use their devices for 30 minutes each day. The next six weeks gave participants a break from daily use, followed by six more weeks of the treatment not received in the beginning of the study.
Participants completed the Tinnitus Functional Index (TFI), and Tinnitus Handicap Inventory (THI) to measure the daily impact of tinnitus. Participants also had their tinnitus loudness assessed during this time.
The team found that when participants received the bi-sensory treatment, they consistently reported improved quality of life, lower handicap scores and significant reductions in tinnitus loudness. These effects were not seen in the control group.
Additionally, more than 60% of participants reported significantly reduced tinnitus symptoms after the six weeks of active – treatment, but not for the control. This matches earlier work from Shore’s team, which showed that the longer participants received active treatment, the greater the reduction in their tinnitus symptoms.
“This study paves the way for the use of personalised, bi-sensory stimulation as an effective treatment for tinnitus, providing hope for millions of tinnitus sufferers,” said Shore.
People in South Africa who fall ill with tuberculosis (TB) often also have other health issues. HIV, which drives much of the TB epidemic in South Africa, is the most obvious co-infection, but people who fall ill with TB are also more likely to have diabetes and mental health problems than the general public.
Another issue that is often mentioned at conferences and in journal articles, but that doesn’t often make the headlines, is the complex set of links between TB and liver problems. With the World Health Organization estimating that in the region of 300 000 people fall ill with TB in South Africa every year, the scale of the issue is likely to be substantial, although we do not have particularly good data on liver problems in South Africa, and even less so on people experiencing TB and liver problems together.
Complex interactions
Broadly speaking, the link between TB and the liver can be divided into two categories. First, there are the liver-related side effects of some TB treatments, and second, there is the interaction between TB and liver conditions such as viral hepatitis. In some cases, TB itself can also cause liver problems directly.
Start with hepatitis. Dr Louisa Dunn, Think TB Provincial TB Technical Lead in KwaZulu-Natal, explains that hepatitis is a general term meaning inflammation of the liver. She says that there are many causes of hepatitis, such as infections, alcohol, or an overdose of certain medications. There is also autoimmune hepatitis, where a person’s own immune system is attacking the liver. “Even lifestyle can cause inflammation in the liver from a build-up of fatty tissue, which is more common in people who are overweight and obese,” she says.
Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are thought to cause significant illness and death in South Africa. According to a study published in 2022, over 1.9 million people in South Africa are living with chronic HBV infection – earlier research put the number at 3.5 million. HBV can be treated and there is an effective childhood vaccine for it that has been used in South Africa since 1995.
Estimates for HCV are less certain than for HBV – an estimate of 400 000 chronic infections was quoted in an HBV and HCV investment case for South Africa. Highly effective cures for HCV infection have been developed over the last decade, although access to these cures remains limited. The Department of Health published viral hepatitis treatment guidelines in December 2019.
Given these numbers, some people in South Africa would simply, by chance, get both TB and hepatitis. But since there are common risk factors, co-infection will be higher than what one would expect purely through chance. HIV infection, for example, increases both a person’s risk of TB and HCV.
“There is no data from South Africa about viral hepatitis and TB co-infection that I am aware of,” says Dr Andrew Scheibe, a Technical Advisor for TB HIV Care and an infectious disease specialist at the University of Pretoria. He points out that people who use drugs and other groups of people who are marginalised, including people experiencing homelessness or people in prison, are at increased risk for these co-infections. The risk of HCV transmission is particularly high when people who inject drugs share needles.
In addition, as Dunn points out, TB itself can also cause hepatitis.
Hepatotoxicity
The picture is further complicated by the fact that several of the medicines used to cure TB have liver-related side effects. Drug-sensitive TB is treated with a combination of four different medicines, while drug-resistant TB is treated with anything from three to eight different medicines.
“Medications used to treat both drug-sensitive and drug-resistant TB can cause hepatitis through drug-induced liver toxicity (hepatotoxicity),” says Dunn. “The presence of other risk factors may further increase the risk of hepatitis in TB patients. These risk factors could be alcohol use, older age, malnutrition, co-infection with HIV or viral Hepatitis B, and taking other potentially hepatotoxic drugs with TB treatment.”
Wieda Human, project coordinator and communications officer at TB advocacy group TB Proof says 3 to 28% of people with TB may experience hepatotoxicity and other side effects. “Those who are already infected with the hepatitis B infection are at an increased risk for hepatotoxicity,” she says.
She refers to a study done in Ethiopia that found having hepatitis B and hepatitis C infection made having TB disease more severe. “This study also found that people with TB who have hazardous alcohol use have a 1.5 times increased risk of developing hepatitis C,” says Human.
What it means for treatment
Dunn says although it is less straightforward to treat a person with TB and hepatitis than a person with just TB, it is important to understand treatment is still available. “It involves establishing the cause for hepatitis and treating this where possible, for instance, treating a viral hepatitis [and TB] co-infection at the same time or [providing] support to reduce alcohol intake. It may involve closer monitoring and follow-up, changes to medications, including stopping treatments either permanently or temporarily, and using alternative more ‘liver-friendly’ treatment regimens,” she says.
“If the hepatitis is stable, then TB can be treated,” Scheibe says. He explains hepatitis B requires long-term treatment (there is no cure), while hepatitis C can be cured with direct-acting antivirals (recently registered in SA, but not yet on the Government Essential Medicines List, so not easily available in the public sector). He says HCV treatment may be delayed until the TB is cured.
No routine screening
South Africa’s National Strategic Plan for HIV, TB, and STIs 2023-2028 under Goal 2 sets out to reduce viral hepatitis morbidity through scale-up of prevention, diagnostic testing, and treatment. However, according to Dunn, screening for viral hepatitis infections, such as HBV, is not part of the current drug-sensitive or drug-resistant TB guidelines.
But she says everyone should be assessed for symptoms and risk factors for liver disease at the start of TB treatment – a sentiment Scheibe shares. According to them, these screenings are however performed at diagnosis of HIV infection before a person is commenced on antiretroviral treatment for HIV, as chronic hepatitis B infection has specific implications for HIV treatment.
“During [TB] treatment, it is critical that clinicians assess people for signs and symptoms that may suggest hepatitis at each visit and educate them on recognising these side effects as well,” says Dunn. “This includes loss of appetite, feeling tired and unwell, nausea, vomiting, abdominal pains, yellowing of the eyes and skin, and darkening of urine.”
Treatment guidelines for drug-induced liver injury are available here. The guidelines focus on the management of suspected drug-induced rash, kidney injury, and liver injury for patients on TB treatment and or antiretroviral treatment.
Scheibe adds that people at high risk for HCV should receive TB screening regularly due to potential exposure to TB (eg if living in closed settings with many people in contexts of high TB prevalence and /or with HIV co-infection).
