Publisher Health

Drugs routinely used during fertility treatments to release eggs do not increase the risk of developing breast cancer, new research has shown.
Researchers from King’s College London, in partnership with King’s Fertility, analysed studies involving 1.8 million women undergoing fertility treatments. These women were followed up in studies for an average period of 27 years and had no increase in the risk of developing breast cancer.
The research, published today in Fertility and Sterility journal, is the largest study to date assessing whether commonly used fertility drugs are for a cancer risk for women.
Fertility treatments can range from using medications to boost the release of an egg in a women’s natural cycle to more complex treatment such as IVF which involves stimulating a patient’s ovarian cycle, extracting eggs from their ovaries, fertilising them with sperm in a laboratory, then transferring the embryo into the womb to develop.
Fertility drugs to stimulate ovaries to release eggs have been used to treat infertility since the early 1960s. Drugs that are used to stimulate the ovaries increase oestrogen hormone production and can act on breast cells. There has been concern that this could turn the cells cancerous, which has led to an uncertainty about the potential risk of infertility drugs causing breast cancer.
The review looked at studies from 1990 to January 2020. Women of all reproductive ages were included in this study and followed up for an average of 27 years following their fertility treatment. ‘Researchers found no significant increase in risk to women exposed to treatment versus untreated women, and untreated women who were infertile.
Study author Dr Yusuf Beebeejaun from King’s College London and King’s Fertility said: “Fertility treatment can be an emotional experience. Patients often ask us if taking ovarian stimulating drugs will put them at increased risk of developing cancers, including breast cancer. To answer that important clinical question, we undertook this review that reports data from nearly 2 million people.”
Dr Sesh Sunkara, senior-author of the paper, from King’s College London and King’s Fertility said ”Our study showed that the use of drugs to stimulate ovaries in fertility treatment did not put women at increased risk of breast cancer. This study provides the evidence needed to reassure women and couples seeking fertility treatments.”
Katy Lindemann, a patient advocate with lived experience of fertility treatment said: “So much of the fear, stress and anxiety associated with fertility treatment is rooted in navigating uncertainty. This study not only gives patients peace of mind at an emotional level, but also enables us to make more informed decisions about treatment risks and benefits at a rational level.”
Dr Kotryna Temcinaite, Senior Research Communications Manager at Breast Cancer Now, said: “Each year around 55,000 UK women get the terrible news that they have breast cancer. We urgently need to learn more about what factors contribute to someone’s risk of developing the disease and stop women dying from breast cancer.
“Previously it was unclear whether fertility drugs affect breast cancer risk, and we do receive calls to our Helpline from women who are concerned that their breast cancer has been caused by fertility treatment. While this analysis of existing published studies does provide welcome reassurance that fertility treatment is unlikely to increase breast cancer risk, further long-term and detailed studies are now needed to confirm these findings.
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Research has found that training stroke survivors to walk at a faster speed during recovery can help improve the brain function that enables people to walk and perform another task simultaneously, known as dual-task walking. The research, led by academics at Oxford Brookes University, was funded by the Stroke Association.
People who’ve had a stroke often struggle to walk and do tasks that involve thinking at the same time, for example, activities such as walking and holding a conversation, or planning what to do next. To effectively walk in the community, cognitive effort is needed to navigate safely and deal with distractions. Many people fail to regain this ability after a stroke.
Dual-task training did not directly improve ability
To improve the ability to walk and think at the same time, rehabilitation approaches have been to directly practice walking and doing something that requires thinking at the same time, known as dual-task training. A previously-run randomised controlled trial led by Oxford Brookes University and the University of Oxford found that this training did not improve people’s ability to dual-task walk any more than just walking training.
Researchers believed that a reason why people struggle with dual-task walking after a stroke may be linked to their walking automaticity — the pattern our brains run which means we don’t have to think about walking. This pattern is linked to the cyclic pattern of walking whereby one step ‘signals’ the next step to follow. If someone walks very slowly this pattern could be disrupted so that walking becomes more like independent steps, rather than a cycle.
Secondary analysis found faster walkers improved dual-task walking
The new research analysed data from the previously-run trial to compare how people who walked slowly and people who walked at faster speeds responded to dual-task training.

Scientists studying a common childhood cancer have made a major breakthrough which could lead to a cure for some youngsters who would not have survived the condition.
An international study, involving Newcastle University, UK, has for the first time found a genetic marker in tumours from patients with high-risk neuroblastoma.
Research, published in the Journal of Clinical Oncology, has identified that alterations in the neuroblastoma’s ALK (anaplastic lymphoma kinase) gene are associated with a significantly poorer prognosis for children with high-risk disease.
Experts say that by identifying this important genetic marker it means patients should be put on ALK inhibitors at the time of diagnosis with the hope of a cure.
Personalised treatment
Professor Deborah Tweddle, from the Newcastle University Centre for Cancer and Honorary Consultant at The Newcastle Hospitals NHS Foundation Trust, led the UK part of the study.

The avian influenza, an acute viral infectious disease that occurs in poultry such as chickens, ducks, and migratory birds, has been reported to be transmittable to humans. It is difficult to control because it spreads among migratory birds that travel to China, Europe, and elsewhere. Once it is transmitted, it spreads rapidly. Disposing infected livestock is not only costly, but also a cause of serious environmental pollution. This is why vaccines against infectious diseases are imperative. To this, a research team in Korea has recently developed a plant-based, adjuvant-free, recombinant protein vaccine that exhibits a strong immune response.
Professor Inhwan Hwang and Ph.D. candidate Shi-Jian Song of the Department of Life Science at POSTECH — in joint research with Professor Chang Seon Song of Konkuk University, Professor Woe-Yeon Kim of Gyeongsang National University, and Eun-Ju Sohn of Bioapp, Inc. — have developed a multivalent vaccine against a variety of avian influenza viruses that does not require any adjuvant. This research was recently published in Journal of Integrative Plant Biology.
Infectious diseases in humans and animals caused by the influenza virus are occurring unpredictably around the world, seriously affecting human health and economic activities like the livestock industry. Various vaccines have been developed and used so far, but concerns have been raised regarding their safety. In particular, the recombinant vaccines enjoy high biosafety and specificity, but have the weakness of low immunogenicity and high production cost compared to inactivated virus or live attenuated virus vaccines.
To this, the joint research team focused on developing multivalent1 vaccines against various avian influenzas based on green vaccine technology. The researchers fabricated a protein trimer (tHA) using plant cells, just like making immune-stimulating drugs from antigenic spikes (haemagglutinin, HA) attached to the influenza virus. By coating this plant-produced tHA on the surface of the inactivated lactococcus without separation or purification, the researchers succeeded in producing bacteria-like particles (BLPs) that carry antigens.
BLPs (tHAs) developed this way showed strong immune responses in mice and chickens without adjuvants. In addition, injections of a bivalent vaccine with two different formulas2 even led to strong immune response to both antigens. This method shows promise to be produced quickly, economically and safely. In fact, the vaccines from this research were applied for patents and are being commercialized with the goal to advance into China and Southeast Asia, as it has gone through a technology transfer to BioApp Co., Ltd.
“Utilizing the green vaccine technology, we have developed a recombinant protein-based vaccine that is safe from exposure to the virus and more,” explained Professor Inhwan Hwang of POSTECH who led the research. “Various strains appear at the same time for influenzas, and this multivalent vaccine can combat such strains.”
This study was conducted with the support of the Ministry of Trade, Industry and Energy and the National Research Foundation of Korea.
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Researchers from the German Center for Infection Research (DZIF) at Charité — Universitätsmedizin Berlin and the University of Bonn have examined the way in which SARS-CoV-2 reprograms the metabolism of the host cell in order to gain an overall advantage. According to their report in Nature Communications, the researchers were able to identify four substances which inhibit SARS-CoV-2 replication in the host cell: spermine and spermidine, substances naturally found in the body; MK-2206, an experimental cancer drug; and niclosamide, a tapeworm drug. Charité is currently conducting a trial to determine whether niclosamide is also effective against COVID-19 in humans.
Viral replication depends on host cell machinery and the use of the host’s molecular building blocks. In order to avoid detection by the immune system, viruses also have to ensure that they can evade cellular surveillance systems. To do this, they manipulate various processes in the infected host cell — and every virus pursues a different strategy. This is why a team of researchers led by PD Dr. Marcel Müller of Charité’s Institute of Virology and Dr. Nils Gassen of the Psychiatry and Psychotherapy Clinic and Outpatient Clinic at the University Hospital Bonn (UKB) have investigated the way in which SARS-CoV-2 reprograms host cells for its own benefit. Their key finding was as follows: The new coronavirus slows down the cell’s own recycling mechanism, a process known as autophagy. The purpose of this ‘auto-digestion’ mechanism is to enable the cell to dispose of damaged cell materials and waste products while recycling usable molecular building blocks for incorporation into new cellular structures.
“In our study, we were able to show that at the same time as using the cell’s building blocks for its own benefit, SARS-CoV-2 deceives the cell by simulating a nutrient-rich status, thereby slowing cellular recycling,” explains first author Dr. Gassen. As part of this work, the researchers undertook a detailed analysis of SARS-CoV-2 infected cells and the lung tissue of COVID-19 patients, studying cellular metabolism and the processing of molecular signals. “It is likely that SARS-CoV-2 uses this to avoid dismantling by the cell. After all, viruses are also subject to autophagic disposal,” adds the study’s last author, DZIF researcher PD Dr. Müller. He adds: “The same reprogramming strategy is also used by the MERS coronavirus, whose autophagy-inhibiting action we were able to demonstrate more than a year ago. However, there are other coronaviruses which, quite in contrast to this, induce autophagy. These mainly infect animals.”
When results from the study suggested that the recycling mechanism might be a potential target for COVID-19 therapy, the researchers tested whether substances which induce cellular recycling also reduce the replication of SARS-CoV-2 inside infected cells. Interestingly, the researchers found four substances which proved effective — all of them already in use in humans. These included the polyamine spermidine, an autophagy-enhancing metabolite which is produced in all human cells and by bacteria in the human gut. It occurs naturally in foods such as wheat germ, soya, mushrooms, and mature cheese and is freely available as a food supplement. When the researchers added spermidine to cells infected with SARS-CoV-2, this resulted in an 85 percent reduction in the numbers of virus particles produced. Similar results were produced by spermine, another polyamine which occurs naturally in the body. This derivative of spermidine was found to reduce viral replication by more than 90 percent in human lung cells and in a human gut model comprising clusters of cells known as ‘organoids’.
“The obvious effects produced by spermidine and, in particular, spermine are certainly encouraging. For one thing, substances which occur naturally in the body are less likely to induce side effects,” says PD Dr. Müller. “Having said that, we worked with pure forms of these substances which are not suitable for medical use. Spermidine, in particular, has to be used at relatively high concentrations to achieve an appreciable effect in cell culture. Many questions therefore remain to be answered before we can consider polyamines as a potential treatment against COVID-19: When used in the body, will it be possible to achieve blood levels high enough to inhibit viral replication in the respiratory tract? And, if yes: would administration before or during the infection be advisable? Are there any side effects? Even so, our findings from cell culture are a good starting point for research involving animal models. Self-medication is not advisable, one of the reasons being that viruses also use polyamines to help boost replication; the correct dosage is therefore crucial. The same applies to fasting, which can stimulate the body’s autophagy process. Given that the body needs energy to mount an immune response, it remains unclear whether fasting is advisable in SARS-CoV-2 infected patients.”
The third substance to prove effective against SARS-CoV-2 was the ‘AKT inhibitor’ MK-2206. The substance is currently at the clinical trial stage and undergoing testing for its tolerability and efficacy against a range of different cancers. In the current study, MK-2206 reduced the production of infectious SARS-CoV-2 virus by approximately 90%. It did so at plasma concentrations which had already been achieved during a previous study. “Based on our data, I would consider MK-2206 as an interesting treatment candidate against COVID-19 which, after a careful analysis of risks and benefits, would justify further study in clinical trials,” explains PD Dr. Müller.
The most pronounced antiviral effect was associated with niclosamide, which the researchers had shown to be effective against the MERS coronavirus during an earlier study. The tapeworm drug was found to reduce the production of infectious SARS-CoV-2 particles by more than 99 percent. “Niclosamide showed the strongest effect in our cell culture-based experiments. What is more, it has been licensed for use against tapeworm infections in humans for a very long time and is well tolerated at potentially relevant doses,” says PD Dr. Müller. He adds: “Out of the four new candidate substances, we consider it to be the most promising one. This is why we are now conducting a clinical trial at Charité to test whether niclosamide might also have a positive effect on people with COVID-19. I am delighted at this development. It shows how quickly findings from basic research can reach patients if research and clinical practice are closely interlinked and work together in an efficient manner.”
The Phase II clinical trial — entitled ‘NICCAM’ — is being led by Prof. Dr. Martin Witzenrath, Deputy Head of Charité’s Department of Infectious Diseases and Respiratory Medicine. The study will test the safety, tolerability, and efficacy of niclosamide combined with camostat (another licenced drug) in patients recently (within the last few days) diagnosed with COVID-19.

In humans, adenoviruses can infect the cells of the respiratory tract, while herpes viruses can infect those of the skin and nervous system. In most cases, this does not lead to the production of new virus particles, as the viruses are suppressed by the immune system. However, adenoviruses and herpes viruses can cause persistent infections that the immune system is unable to completely suppress and that produce viral particles for years. These same viruses can also cause sudden, violent infections where affected cells release large amounts of viruses, such that the infection spreads rapidly. This can lead to serious acute diseases of the lungs or nervous system.
Automatic detection of virus-infected cells
The research group of Urs Greber, Professor at the Department of Molecular Life Sciences at the University of Zurich (UZH), has now shown for the first time that a machine-learning algorithm can recognize the cells infected with herpes or adenoviruses based solely on the fluorescence of the cell nucleus. “Our method not only reliably identifies virus-infected cells, but also accurately detects virulent infections in advance,” Greber says. The study authors believe that their development has many applications — including predicting how human cells react to other viruses or microorganisms. “The method opens up new ways to better understand infections and to discover new active agents against pathogens such as viruses or bacteria,” Greber adds.
The analysis method is based on combining fluorescence microscopy in living cells with deep-learning processes. The herpes and adenoviruses formed inside an infected cell change the organization of the nucleus, and these changes can be observed under a microscope. The group developed a deep-learning algorithm — an artificial neural network — to automatically detect these changes. The network is trained with a large set of microscopy images through which it learns to identify patterns that are characteristic of infected or uninfected cells. “After training and validation are complete, the neural network automatically detects virus-infected cells,” explains Greber.
Reliably predicting severe acute infections
The research team has also demonstrated that the algorithm is capable of identifying acute and severe infections with 95 percent accuracy and up to 24 hours in advance. Images of living cells from lytic infections, in which the virus particles multiply rapidly and the cells dissolve, as well as images of persistent infections, in which viruses are produced continuously but only in small quantities, served as training material. Despite the great precision of the method, it is not yet clear which features of infected cell nuclei are recognized by the artificial neural network to distinguish the two phases of infection. However, even without this knowledge, the researchers are now able to study the biology of infected cells in greater detail.
The group has already discovered some differences: The internal pressure of the nucleus is greater during virulent infections than during persistent phases. Furthermore, in a cell with lytic infection, viral proteins accumulate more rapidly in the nucleus. “We suspect that distinct cellular processes determine whether or not a cell disintegrates after it is infected. We can now investigate these and other questions,” says Greber.
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Acrylamide, which is extensively used in industries, causes peripheral neuropathy or encephalopathy. Now, scientists from Japan examined the response against oxidative stress in acrylamide-induced neurotoxicity and found that nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the immune system and response to oxidative stress, was at the center of this toxicity. They found that Nrf2 plays a protective role by increasing the expression of protective genes and decreasing that of pro-inflammatory genes.
Acrylamide is a toxic chemical compound that affects the nervous system. Not only is it widely used in industries such as paper production, plastics, and wastewater management, but it is also a byproduct of commonly used food processing methods, which makes human exposure to acrylamide inevitable. Therefore, many studies have focused on understanding the toxic effects of acrylamide and our body’s response to them. Generally, in response to toxicity, the body’s cells release protective factors and antioxidants to remedy the damage. This response is activated by various cellular machinery. One such activator is a protein called “nuclear factor erythroid 2-related factor 2” (Nrf2), which is a master regulator of the response to oxidative stress and the immune system.
In a recent study, a team of scientists, led by Prof. Gaku Ichihara from Tokyo University of Science, reported the role of Nrf2 in acrylamide-induced neurotoxicity. Prof. Ichihara states, “Our study showed that Nrf2 has a protective role against neurologic damage and suggests it is through activation of antioxidant stress genes and suppression of proinflammatory cytokine genes.”
In their study published in the journal Toxicology, Prof. Gaku Ichihara, along with his colleagues Prof. Masayuki Yamamoto from Tohoku University, Prof. Ken Itoh from Hirosaki University, Associate Prof. Seiichiroh Ohsako from The University of Tokyo, and Prof. Sahoko Ichihara from Jichi Medical University, used mice models to study the role of Nrf2 in acrylamide-induced neurotoxicity. They tested their hypothesis that when Nrf2 gene is removed, the neurotoxic effects of acrylamide will be amplified. For this, they developed “knockout” mice that could not produce Nrf2, and gave the Nrf2-knockout mice and a set of counterpart “wild-type” mice that could produce Nrf2 different concentrations of acrylamide for 4 weeks. Then, they compared the neurotoxicity between both groups of mice using various sensory and motor tests, immunohistochemistry, and protein and gene expression analyses.
The scientists found that the Nrf2-knockout mice had severe neurotoxic effects such as sensory and motor system dysfunction and axonal damage. While these mice produced fewer antioxidants and protective factors in response to acrylamide, they also showed enhanced release of pro-inflammatory chemicals, called “cytokines,” in the brain, which can potentially cause additional damage. Additionally, as different doses were given to the mice, the scientists also determined that the neurotoxicity was dose-dependent.
Previous studies have established the role of Nrf2 as a master regulator of protective genes but this study explained the specific mechanisms of immune response to acrylamide-induced toxicity, with Nrf2 at the center of it all. As Prof. Ichihara states, “The results document the first known morphological and neuro-functional evidence of the regulatory role of Nrf2 in acrylamide-induced neurotoxic effects in mice.”
The findings of this study are also immensely valuable in the field of disease biology, as recent studies have shown a link between air pollution and Alzheimer’s disease. Since the air contains other acrylamide-like chemical pollutants with similar neurotoxic effects, the study’s findings could prove useful in the prevention of Alzheimer’s disease.
Prof. Ichihara and his team’s study is certainly a timely one, as reports of acrylamide intoxication are on the rise and further research is required to better understand the specific mechanisms by which the body protects itself from harm.
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A blood test that can detect tiny amounts of circulating cancer DNA may be able to identify risk of cancer recurrence and guide precision treatment in bladder cancer following surgery, according to a clinical study led by Professor Tom Powles from Queen Mary University of London and Barts Health NHS Trust. The findings from the study, published in Nature, may change our understanding of cancer care following surgery.
The study found that patients with urothelial cancer who had a particular cancer DNA marker in their blood following surgery to remove their tumour had a higher likelihood of cancer relapse. These patients could benefit from subsequent treatment with an immunotherapy called atezolizumab.
Globally, there were approximately 573,000 cases of and 212,000 deaths from bladder cancer in 2020. Surgery is often among the first treatments for advanced bladder cancer that has grown into the muscle layer of the bladder wall (muscle-invasive). However, relapse rates after surgery are high as some cancer cells can be left behind when the tumour is removed. These remaining cancer cells, known as molecular residual disease (MRD), increase the chances of a patient’s cancer reoccurring as the cells can spread and establish tumours elsewhere in the body.
This study, funded by F. Hoffmann-La Roche Ltd./Genentech, Inc, and Barts Cancer Institute/Queen Mary University of London evaluated treatment outcomes in a subgroup of patients (comprising 581 individuals) who were enrolled onto a randomised phase III trial (IMvigor010) and a phase II study (ABACUS) which investigated whether the drug atezolizumab could reduce cancer recurrence in high-risk muscle-invasive urothelial carcinoma.
To identify patients with increased likelihood of MRD following surgery, a blood test was used to detect the presence or absence of circulating tumour DNA (ctDNA) — tumour-derived fragments of genetic material that can escape into the bloodstream and are considered to be indicative of MRD. The team found that patients with ctDNA-positive blood tests after surgery were at higher risk of cancer recurrence than those who were ctDNA-negative.
Treatment with atezolizumab did not significantly improve disease-free survival (DFS; the length of time after treatment during which no sign of cancer is found) nor overall survival (OS) in the whole IMvigor010 study population; however, in the ctDNA-positive subgroup of patients evaluated in this study, treatment with atezolizumab compared with observation alone significantly improved DFS (5.9 vs 4.4 months) and OS (25.8 vs 15.8 months). The outcomes in patients who were ctDNA-negative did not appear to differ whether they received atezolizumab or not.
Lead researcher, Tom Powles, Professor of Genitourinary Oncology at Queen Mary’s Barts Cancer Institute and Director of Barts Cancer Centre at Barts Health NHS Trust, said:
“These novel findings demonstrate ctDNA as a marker for residual disease and response to atezolizumab. We also found ctDNA measurement to be more accurate than traditional radiology at identifying disease relapse. These findings may change our understanding of post-surgical cancer care and, if validated in this setting as well as across tumour types, they may also change clinical practice.”
It is difficult to determine which patients harbour MRD and which are cured after surgery. As a result, many patients who are cured by surgery are unnecessarily exposed to toxicities from additional treatments, and other patients with residual disease may not receive potentially beneficial treatment until disease progression is detectable by imaging. The findings from this study suggest that detection of ctDNA shortly after surgery may overcome these clinical limitations by enabling early identification of patients harbouring MRD.
Initiating personalised treatment based on the identification of MRD rather than treating unselected patients or waiting for relapse would be a significant change in cancer treatment. Further studies will now be required to validate and expand the clinical utility of this method, and to determine whether ctDNA measurement could aid in directing post-surgical treatment to those who need it.
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Materials provided by Queen Mary University of London. Original written by Bethan Warman. Note: Content may be edited for style and length.

Helsinki University research group used live tissue imaging for the first time to visualise the emergence of the mammary gland.
Despite long-standing interest, the cellular mechanisms driving the initiation of mammary gland development have remained elusive for decades, mostly due to technical limitations in studying dynamic cell behaviors in live tissues. Recent advances in microscopic methods and availability of various mouse models allowed the research group of Marja Mikkola from HiLIFE Institute of Biotechnology, University of Helsinki to address this question. This is the first time when live tissue imaging has been used to visualise the emergence of the mammary gland.
Mammary gland is the class-defining organ of mammals, yet we know surprisingly little how its development commences. In their recent study published in Journal of Cell Biology, the research group of Marja Mikkola used time-lapse imaging to show that the growth of the mammary bud is primarily fueled by migration of cells to the bud. In contrast, although increase in cellular size and cell proliferation contribute to this process, the role of these mechanisms remains minor.
“Interestingly, mammary bud cells, unlike most of other skin derivatives such as hair follicle and tooth bud, do not divide for several days, indicating that this might be a unique feature of early mammary gland development” says graduate student Ewelina Trela, the lead author of the study. “However, we do not yet know why this happens,” she continues.
Mammary buds use a previously undescribed mechanism for invagination
Tissue invagination, or tissue folding inwards into the underlying stroma, is a fundamental mechanism that occurs to generate the architecture of many organs. In the same piece of work, the authors describe a novel mechanism for tissue invagination.
“Using confocal fluorescence microscopy, we found thin and elongated epidermal keratinocytes surrounding mammary bud in a rim like fashion: their appearance and disappearance coincided with the invagination process suggesting that these cells, named ring cells, could be functionally important” details principal investigator Marja Mikkola.
Next, the Mikkola group teamed up with the group of Sara Wickström at HiLIFE and Faculty of Medicine, University of Helsinki to establish live imaging of the forming mammary bud, which confirmed that ring cells move circumferentially around the mammary bud.
The study also revealed that the ring cells exert contractile force through the actomyosin network, via non-muscle myosin IIA (NMIIA). The functionality of ring cells was impaired in NMIIA deficient mice leading to compromised mammary bud shape. Whether other developing organs utilize a similar cellular mechanism for invagination remains an open question.
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A research team led by Professor Hongzhe SUN, Norman & Cecilia Yip Professor in Bioinorganic Chemistry and Chair Professor from Research Divison for Chemistry and Department of Chemistry, Faculty of Science, in collaboration with Dr Richard Yi-Ysun KAO, Associate Professor from the Department of Microbiology, Li Ka Shing Faculty of Medicine, and Dr Aixin YAN, Associate Professor from School of Biological Sciences, the University of Hong Kong (HKU), discovers that silver (Ag)-based antimicrobials can effectively combat antibiotic resistant Staphylococcus aureus by targeting multiple biological pathways via functional disruption of key proteins and can be further exploited to enhance the efficacy of conventional antibiotics as well as to resensitise methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics.
The study resolves the long-standing question of the molecular targets of silver in Staphylococcus aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a new approach for combating antimicrobial resistance. The ground-breaking findings are now published in a leading multidisciplinary science journal, Nature Communications.
Background
Antibiotics are medicines designed to kill bacteria and treat bacterial infections. Antibiotic resistance occurs when bacteria adjust in response to the misuse or overuse of these medicines, and it has become one of the biggest public health challenges in this era. At least 2.8 million people get an antibiotic-resistant infection annually in the US, and more than 35,000 people die from it.
Staphylococcus aureus, a round-shaped Gram-positive bacterium, is a dangerous and versatile pathogen for humans and is estimated that approximately 30% of the human population are asymptomatic nasal and long-term carriers. Staphylococcus is the causative agent of a variety of diseases, such as skin infection, food poisoning, bone/joint infection, and bacteremia, ranging from subacute superficial skin infection to life-threatening septicemia. The rise in incidence has been accompanied by an increase in antibiotic-resistant strains, especially MRSA. Moreover, the outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic may further increase antimicrobial resistance due to the heavy use of antibiotics to treat patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2). Given the rapid emergence of drug-resistant Staphylococcus aureus but a lack of antibiotic-development pipeline, alternative strategies are urgently needed to combat antibiotic-resistant Staphylococcus aureus.
Key findings
Metal ions have been historically used as antimicrobial agents owing to their inherent broad-spectrum antimicrobial properties and less chance of resistance. There is a growing interest in revitalising metal-based compounds as promising alternatives to tackle the antimicrobial resistance crisis. Silver ions (Ag+) and silver nanoparticles (AgNPs) have been used as antimicrobial agents for centuries and are still being widely used in the healthcare and food industry. Previously, the team has built a technical platform named LC-GE-ICP-MS to systematically identify Ag+-proteome in Escherichia coli and developed a strategy named metabolome reprogramming to enhance the efficacy of antibacterial metallodrugs (PLoS Biol., 2019, 17, e3000292; Chem. Sci., 2019, 10, 7193-7199; Chem. Sci., 2020, 11, 11714-11719).
In this study, using the customised approach of LC-GE-ICP-MS, the team successfully separated and identified 38 authentic Ag+-binding proteins (Ag+-proteome) in Staphylococcus aureus at the whole-cell scale. In combination with bioinformatics analysis and systematic biochemical characterisation, they demonstrate that Ag+ exploits a shotgun action through targeting multiple proteins, thus interfering with multiple pathways, including glycolysis, oxidative pentose phosphate pathway (oxPPP), and reactive oxygen species (ROS) stress defence system, to exert its bactericidal effect against Staphylococcus aureus. Further studies unveiled that oxPPP served as a vital pathway targeted by Ag+ in Staphylococcus aureus, with 6PGDH identified as the key enzyme involved in the inhibitory effects of Ag+ against Staphylococcus aureus. They resolved the first crystal structures of 6PGDH from Staphylococcus aureus both in substrate-bound and Ag-bound forms and revealed that Ag+ abolished the enzymatic activity of 6PGDH through targeting Histidine 185 in the active site and morphing its catalytic pocket. This study resolves the long-standing question on the molecular targets and mode of action of silver against Staphylococcus aureus. Such a unique mode of action of silver via targeting multiple pathways confers the inability to select silver-resistant Staphylococcus aureus and endows it with the sustainable efficacy against Staphylococcus aureus.
Based on the uncovered molecular mechanism, they further demonstrate that Ag+/AgNP can potentiate the efficacy of a broad range of antibiotics, resensitise MRSA to antibiotics, and slow down the evolution of antibiotic resistance in Staphylococcus aureus. Therefore, a combination of antibiotics with silver or other metal-based compounds or nanomaterials could serve as a promising strategy to suppress the selection effects of antibiotics, thus preventing the occurrence of primary antibiotic resistance and extending the lifespan of conventional antibiotics to relieve the current crisis of antibiotic resistance.
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