Tuesday, 30 April 2019

Seeking Action to Combat a Major Child Killer: A Global `Pandemic’ of Fake Drugs


There is urgent need for a new international effort to combat a global surge in poor quality and outright fake medicines that kill more than 250,000 children each year and extract some $200 billion from developing country economies, according to an exhaustive analysis published today in the American Journal of Tropical Medicine and Hygiene.

The assessment from a team of experts from the public and private sector concludes that a “pandemic” of falsified and substandard drugs for treating malaria, pneumonia, hypertension and other diseases has become a public health emergency. It cites evidence that fake malaria drugs alone cause up to 155,000 children to die every year and that a similar number die from low-quality or counterfeit antimicrobial drugs prescribed to treat pneumonia.

The study also notes that fake drugs, often peddled over the Internet and sometimes linked to organized crime and terrorist groups, include medicines for heart disease, erectile dysfunction and cancer, along with fake prescription opioids.

The authors call for more support for a drug surveillance program managed by the World Health Organization and for adding a milestone to the United Nations Sustainable Development Goals in which governments would guarantee that, by 2030, at least 90 percent of medicines sold in their countries are high quality. The authors also seek support for developing affordable tools for testing drug quality at the point of sale, and they recommend a multilateral treaty on “medicine crime” and drug quality.

See: http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0981

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 29 April 2019

Advances in antimicrobial research


In the last two decades, the rate at which bacteria are becoming resistant to current antibiotic treatments has substantially increased. Antibiotic resistance is a form of drug resistance whereby some sub-populations of a microorganism are able to survive after exposure to one or more antibiotics. One of the triggers for this is due to the overuse of use medicines, as arises from mis-prescribing or the use of antibiotics with farm animals.

This trend is threatening the ability of medical staff to carry out routine operations or transplants in the future, or for medics to treat patients. This has been compounded not only by microorganisms that are resistant to one antimicrobial or another, but due to the rise of multi-drug resistant microorganisms (the so-termed ‘super bugs’). Prominent examples include MRSA (methicillin-resistant Staphylococcus aureus), VISA (vancomycin-intermediate S. aureus), VRSA (vancomycin-resistant S. aureus), ESBL (Extended spectrum beta-lactamase), VRE (vancomycin-resistant Enterococcus) and MRAB (multidrug-resistant Acinetobacter baumannii).

To understand the current state of antimicrobial research, Tim Sandle has written a new article.

"Renewed focus on the need to develop new antimicrobials and new methods for treating patients with bacterial infections. The current state of the antibiotic market is troubling. Funding is scarce, big pharmaceutical companies are shuttering their research and development programs and much of the burden is being left to smaller companies with fewer resources, or the initiatives are coming from government-backed programmes in academia. Despite the less-than-ideal rate of innovation, there are some interesting strands of work emerging (4). This articles surveys some of the more recent developments."




The reference is:

Sandle, T. (2019) Advances in antimicrobial research, Microbioz India, 5 (2): 14-22

The article can be accessed here: http://www.microbiozindia.com/microbiology-news/advances-in-antimicrobial-research-february-2019-cover-story.htm#sthash.Ns5gq4Tj.qwVmqFhv.dpbs

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 28 April 2019

Excessive hygiene promotes resistance to antibiotics


The number of people who become ill and die from antibiotic-resistant germs is increasing worldwide. The World Health Organization WHO sees understanding the spread of antibiotic resistance and developing countermeasures as one of the most important global challenges. Against this background Gabriele Berg, who heads the Institute of Environmental Biotechnology at Graz University of Technology (TU Graz), has initiated an interdisciplinary cooperation project in her research project Plant-associated microbial communities in indoor environment which is funded by the Austrian Science Fund (FWF).

The research group investigated microbial control -- the degree of cleaning and hygiene measures -- and how it influences the development of resistances. Research was carried out together with national partners of the Medical University of Graz in the framework of the BioTechMed-Graz inter-university cooperation and international partners.

The researchers compared the microbiome and the resistome -- i.e. all existing microorganisms and antibiotic resistances -- at the intensive care unit of the Department of Internal Medicine at University Hospital Graz with clean rooms subject to strong microbial control in the aerospace industry and with public and private buildings which have hardly any microbial controls. The analyses show that microbial diversity decreases in areas with high levels of hygiene but that the diversity of resistances increases. 'In environments with strong microbial control in the intensive care unit and industrially used clean rooms, there are increasing antibiotic resistances which show a high potential for combining with pathogens,' explains Dr Alexander Mahnert, director of studies at the Institute of Environmental Biotechnology of TU Graz, who is currently conducting research at the Medical University of Graz.
The results indicate that a stable microbial diversity in clinical areas counteracts the spread of resistances. 'The microbial control of pathogens is already being successfully used in cultivated plants and also in humans in the framework of stool transplantation. Our study provides an initial foundation to pursue such ideas in indoor areas in the future,' says Berg. Regular airing, houseplants, the deliberate use of useful microorganisms and the reduction of antibacterial cleaning agents could be the first strategies in maintaining or improving microbial diversity.

In a subsequent step, the research team at Graz University of Technology would like to develop and implement biotechnological solutions for a tailor-made microbial diversity.

See:

Alexander Mahnert, Christine Moissl-Eichinger, Markus Zojer, David Bogumil, Itzhak Mizrahi, Thomas Rattei, José Luis Martinez, Gabriele Berg. Man-made microbial resistances in built environments. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-08864-0

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 27 April 2019

Novel potent antimicrobial from thermophilic bacterium


Microbiologists have discovered a new glycocin, a small antimicrobial peptide with a sugar group attached, which is produced by a thermophilic bacterium and is stable at relatively high temperatures. They also succeeded in transferring the genes required to produce this glycocin to an E. coli bacterium. This makes it easier to produce and investigate this compound, which could potentially be used in biofuel production.

The rise of antibiotic resistance has spurred the search for new antimicrobials. Bacteriocins -- peptide toxins produced by bacteria to inhibit growth in similar or related bacterial strains -- are a possible alternative to the more traditional antibiotics. Bacteriocins would also be useful to protect high-temperature fermentations mediated by thermophilic bacteria. But this would require the use of bacteriocins that are stable at higher temperatures.

'That is why we were interested to find that the thermophilic bacterium Aeribacillus palladius, isolated from the soil above an oil well in Lithuania, appeared to produce an antibacterial peptide,' says University of Groningen Professor of Molecular Biology, Oscar Kuipers. Thus far, purification and identification of the compound had not been successful. Therefore, Ph.D. student Arnoldas Kaunietis from Vilnius University spent almost two years in Kuipers' lab to solve the mystery. He is the first author on the new paper.

By analyzing genomic information from the Lithuanian bacteria using BAGEL4 software, developed by Anne de Jong and Auke van Heel in Kuipers' group, genes that are responsible for the production of the bacteriocin were discovered and the final gene product was named pallidocin. The BAGEL4 software searches for gene clusters with the potential ability to produce novel antimicrobials.

The antimicrobial turned out to be a glycocin, belonging to a class of post-translationally modified peptides. This means that after its production, one or more functional groups are added to the peptide. In the case of glycocins, this functional group is a sugar. 'Only five other glycocins were known thus far,' says Kuipers.

In order to facilitate further research and engineering of this peptide, the genes responsible for the production of pallidocin were transferred to E. coli BL21 (DE3) bacteria. 'The expression of the genes worked well, which is a real breakthrough, as it is difficult to express a whole antimicrobial gene cluster from a gram-positive bacterial strain directly in a gram-negative bacterium and to get the product secreted.'

After isolating pallidocin, the scientists were able to confirm that it is highly thermostable and exhibits extremely strong activity against specific thermophilic bacteria. Furthermore, by using the sequence of pallidocin biosynthesis genes in BAGEL4, two similar peptides were discovered in two different strains of Bacillus bacteria. These peptides, named Hyp1 and Hyp2, were also successfully expressed in the E. coli strain. 'This shows that the expression system works well for various glycocins; it is able to produce them in vivo', says Kuipers.
Pallidocin might be useful in high-temperature fermentations, which are used to produce biofuels or chemical building blocks. The higher temperature makes it easier to recover volatile products such as ethanol but also reduces the risk of contamination with common bacteria. However, contamination with thermophilic bacteria is possible. 'Both pallidocin and Hyp1 appear to be active against thermophilic bacteria and some Bacillus species,' says Kuipers. And there could be more applications: 'Contamination by thermophiles is also a problem in the food industry.'

See:

Arnoldas Kaunietis, Andrius Buivydas, Donaldas J. Čitavičius, Oscar P. Kuipers. Heterologous biosynthesis and characterization of a glycocin from a thermophilic bacterium. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-09065-5

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 26 April 2019

A multicellular way of life for a multipartite virus


Scientists have shown that different segments of a virus genome can exist in distinct cells but work together to cause an infection. This discovery upturns a fundamental model in virology that a virus genome enters and replicates within a single cell and then moves on to replicate in another.

The findings, published in the open-access journal eLife, upturn a fundamental model in virology that a virus genome enters and replicates within a single cell and then moves on to replicate in another.

Multipartite viruses are intriguing viral systems because their genome is divided into several segments and each is enclosed within a distinct virus particle. It has long been believed that all of the genome segments must move together from cell to cell to cause an infection. But the new study shows this is not the case.

“The chances of a multipartite virus losing an essential genome segment during transmission are estimated to be so high, its ability to successfully cause an infection has been a long-standing mystery,” says first author Anne Sicard, Postdoctoral Researcher at the National Institute for Agricultural Research (INRA), France. “We set out to test a bold possibility: can this virus successfully infect a host even if its genome segments are not together within individual cells?”

To investigate this, the scientists studied the faba bean necrotic stunt virus, which has eight distinct genome segments, and used fluorescent probes to detect the presence of the different viral segments in individual cells of the faba bean plants. Interestingly, the team found that distinct segments are most often found in different cells. This even applied to segments of the genome that code for vital functions such as replication, encapsidation (the process of enclosing viral DNA in a protective coat) and movement of the virus between cells.

These results suggest that the virus can function while its genome segments appear in distinct cells, but more evidence was needed. To further counter the possibility that all genome segments are replicated as a single system within individual cells, the team sought to show that the segments could independently accumulate in different cells. They labelled the segments responsible for replication and encapsidation with red and green fluorescence and measured the amounts in different cells to see whether accumulation of one segment in the pair was dependent on the other. They found no link between the amounts of the two different segments at either early or later stages of infection, showing that accumulation of the segments was independent.

To make sense of these findings, they assumed that a viral function can act in a cell even where its genome segment is not present. To test this, they focused on the genome segment responsible for replication (R) and searched for the molecule it encodes – M-Rep – in cells where another segment (S) is replicated. Although the segment R was only detectable in a minority of these cells (about 40%), its product M-Rep was found in nearly 85%. This suggests that either the M-Rep protein itself, or transcripts of the genome segment that makes it, is produced in cells where the segment R is present and then travels to other cells of the host.

“Altogether, we have shown that distinct segments of a virus’ genome are not necessarily together within individual host cells, and that accumulation of one genome segment in a cell is entirely independent of accumulation of the others,” concludes senior author Stéphane Blanc, Research Director at INRA. “It is conceivable that this ‘multicellular’ way of life could be adopted in numerous viral systems and opens up an entirely new research horizon in virology.”
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 25 April 2019

From The Floor Up: The Battle to Control HAIs


Floors, often overlooked in the past as a major factor of environmental contamination leading to increased HAI rates, are, in fact, a contributor to this very expensive and life-impacting problem. Studies have shown that floors harbor HAI pathogen organisms. These pathogens may not be neutralized by using mops that bind disinfectants or may be transported through unexpected means, including socks or laundered mops damaged by the laundering process and reducing their ability to effectively clean or disinfect the floor.

Download this whitepaper, which discusses:
  • Human and financial implications of HAIs.
  • Microfiber laundered mops retain residual pathogens.
  • Impact of laundry processes on microfiber’s structure and efficacy.
  • Moving to single-use mops.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 24 April 2019

Results of Trial to Stem Hospital-Acquired Bacterial Infections Published


New findings from a large, randomized clinical trial that compared two infection control techniques are already being incorporated into practice within the network of U.S. community hospitals where the trial took place.

The trial evaluated whether daily bathing with the antiseptic soap chlorhexidine (CHG)—and in those patients with methicillin-resistant Staphylococcus aureus (MRSA), adding the nasal antibiotic mupirocin—more effectively reduced hospital-acquired bacterial infections than bathing with ordinary soap and water. While no statistically significant difference between the two intervention groups was seen within the population overall, the researchers did find that one subset of patients—those with medical devices—experienced a substantial benefit if they received the CHG/mupirocin intervention.

The ABATE (Active Bathing to Eliminate) Infection trial was initiated through the National Institutes of Health’s Common Fund program and was managed by the National Institute of Allergy and Infectious Diseases (NIAID), an NIH component. Results of the study, which involved about 330,000 adult patients in non-intensive care units in the HCA Healthcare system, appear today in The Lancet. Susan S. Huang, M.D., M.P.H., of the University of California Irvine School of Medicine, led the research team.

Previous clinical trials in intensive care units (ICUs) had shown that hospital-acquired infections could be dramatically reduced through such practices as CHG bathing, noted Dr. Huang. “Because there was a clear benefit with bacterial decolonization in the ICU setting, we pursued this trial to determine if similar interventions would reduce hospital-acquired infections in non-ICU settings, where the majority of such infections occur,” she said. Decolonization refers to the removal of skin-surface bacteria that are normally harmless, but that may enter the bloodstream following surgery or other procedures and cause infection, including life-threatening sepsis.

During a five-month recruitment period, 53 community hospitals (comprising 194 non-ICU units) throughout the HCA Healthcare system were randomized to either the routine bathing arm or the CHG bathing plus mupirocin arm of the study. Five hospitals withdrew, leaving 24 hospitals in each arm of the 21-month-long intervention. During that period, the 330,000 patients enrolled in the trial had 1.3 million days of hospital care.

The study was implemented as a quality improvement effort using staff and caregivers already working in the units. “We provided resources including coaching calls, training binders, and instructional handouts for patients and caregivers, as well as a training video with actors that demonstrated how caregivers might answer patient concerns about CHG bathing,” said Dr. Huang. Computer-based training was provided to 14,000 staff members in the participating hospitals. On request, trial team members visited sites to demonstrate CHG bathing techniques, but investigators were not on-site throughout the trial.

Within the overall study population, the research team found no statistically significant difference between the study arms. However, patients with medical devices, such as central venous catheters or lumbar drains, benefitted from the CHG/mupirocin intervention. Among that subset of patients, investigators recorded a 30 percent decrease in bloodstream infections and a nearly 40 percent decrease in antibiotic-resistant bacteria, including MRSA and vancomycin-resistant enterococcus, compared to rates seen in similar patients in the standard bathing arm of the trial. The benefit of CHG bathing for patients with devices is notable, said Dr. Huang. Although they represented only 12 percent of the total non-ICU patient population, patients with devices had a disproportionately high risk for bacterial infection: they accounted for 37 percent of MRSA and VRE clinical cultures and more than half of all bloodstream infections.

“The ABATE Infection trial is a good example of what a large-scale, pragmatic clinical trial can achieve within a relatively short period of time,” said NIAID Director Anthony S. Fauci, M.D. “This trial also highlights the value of partnerships between academic investigators and healthcare delivery organizations,” he said.

Classic clinical trials typically recruit and enroll patients one by one, and are often costly, labor-intensive and time-consuming. According to Dr. Huang, pragmatic trials complement the strengths of classic clinical trials, but because they are performed under ‘real world’ conditions—for example, by weaving quality improvement strategies into existing care routines—they are usually less expensive.

“The results of the ABATE Infection trial are already being incorporated into infection prevention efforts,” said Jonathan Perlin, M.D., Ph.D., chief medical officer of HCA Healthcare and a co-author of the new study. “The HCA system is using this decolonization strategy as a best practice for patients with medical devices across our 179 affiliated hospitals,” he said.


In addition to Dr. Huang and collaborators at the University of California Irvine, the study team included investigators from HCA Healthcare, Harvard Medical School and Harvard Pilgrim Health Care Institute, Rush Medical College and the Centers for Disease Control and Prevention. It was conducted as part of the NIH Collaboratory for pragmatic clinical trialsto address questions of major public health importance. The antiseptic product was contributed by Sage Products and MoInlycke. The companies providing product to the trial had no role in the design, conduct, analysis or publication of the ABATE Infection trial.


Reference: SS Huang et al. Chlorhexidine versus routine bathing to prevent multidrug-resistant organisms and all-cause bloodstream infection in general medical and surgical units (ABATE Infection trial): a cluster-randomised trial. The Lancet DOI: 10.1016/S0140-6736(18)32593-5 (2019).

Source: NIH

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 23 April 2019

Short Regimen for Preventing TB Found Safe When Co-administered with New First-line HIV Drug


In an important moment for tuberculosis (TB) control, a new study finds that a shorter regimen to prevent TB can be safely co-administered with dolutegravir (DTG)—the first-line drug to treat HIV in many high-burden TB countries. Presented today at the Conference on Retroviruses and Opportunistic Infections (CROI), the study found that weekly administration of rifapentine and isoniazid (3HP) for three months in adults with HIV taking DTG was well-tolerated, with no need for dose-adjustment. The findings put to rest fears of potential drug interactions with DTG and pave the way for scale-up of the 3HP regimen in 12 high-burden TB countries across three continents.

“We’ve known for some time that preventive therapy for TB is a critical component of any effort to control the TB epidemic,” said Prof. Gavin Churchyard, group CEO of the Aurum Institute and co-principal investigator on the study. “But current treatment options are too long and potentially more toxic. These findings will allow us to move forward with co-administration of 3HP and DTG, offering the best treatment options to those who need it the most.”

The study, funded by Unitaid and carried out in South Africa by the Aurum Institute and the Johns Hopkins University Center for TB Research, looked at the safety and pharmacokinetics of giving 3HP with DTG. Researchers enrolled 60 adults with HIV, who received DTG for eight weeks, then began 3HP; after completion of 3HP, all participants were followed for four more weeks. Overall, co-administration of DTG and 3HP was well-tolerated.


Read more:

Monday, 22 April 2019

Bacterial Endotoxin Risks to Pharmaceutical Water Systems: Three Case Studies


Well-maintained and operated water systems should not see endotoxin detected regularly. Where endotoxin detection occurs, this is due to a special cause event, signifying that something untoward has occurred. To illustrate what can sometimes occur, a short article by Tim Sandle presents three cases studies.

The reference and link is:

Sandle, T. (2019) Bacterial Endotoxin Risks to Pharmaceutical Water Systems: Three Case Studies, Rapid Microbiology. Online article at: https://www.rapidmicrobiology.com/news-temp-link/Mjg0Mw 



Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 21 April 2019

`SuperTowel’ Shows Potential to Limit Spread of Disease in Humanitarian Crises


A new hand-washing product dubbed the SuperTowelTM could become a useful complementary tool for fighting disease outbreaks in humanitarian crises where limited access to soap and clean water aggravates the spread of conditions like diarrhea and cholera, according to a new study published today in the American Journal of Tropical Medicine and Hygiene.

A team led by researchers from the London School of Hygiene and Tropical Medicine found that various prototypes of the hand-towel-size SuperTowel, made from high-tech microfiber that can neutralize many disease-causing microbes, were more effective than hand-washing with soap at removing bacteria. The product was developed for situations like crowded refugee camps, war-torn cities, and natural disasters where diseases spread by hands that have come into contact with fecal matter are a major humanitarian challenge.

The SuperTowel has to be dipped in a small amount of water to work, but the researchers found it required much less water than normal handwashing. The current study tested the towel in volunteers whose hands had been deliberately exposed to a relatively harmless strain of Escherichia coli (E. Coli)bacteria that, in other forms, can cause severe diarrhea. The researchers said additional studies are needed in more challenging conditions.

See: http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0860

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 20 April 2019

‘Sentinel Chickens’ Shed Light on US Resurgence of Deadly Mosquito-Borne Virus



Analysis of “sentinel chickens”—flocks deployed specifically to detect the presence of mosquito-borne diseases—reveals the Florida Panhandle as the likely epicenter of a rare but deadly virus that has re-emerged in recent years to spread as far north as Canada, according to a new study published recently in the American Journal of Tropical Medicine and Hygiene.

Researchers at Vanderbilt University Medical Center, in collaboration with the Florida Department of Health and the University of South Florida, investigated transmission patterns for Eastern equine encephalitis virus, or EEEV, the deadliest mosquito-borne disease in North America. After decades of sporadic activity, the virus re-emerged about 14 years ago with a spate of cases from Florida to New England and into Nova Scotia, Canada. Infections, which can sicken humans and horses, can progress to a dangerous brain infection. And while that’s rare in humans—only about 70 cases have been reported since 2008—the fact that 30 (43 percent) of victims died has prompted intensive surveillance.

In the current study, researchers analyzed blood samples from thousands of chickens used by state health officials across Florida from 2005 to 2016 to alert them to the presence of EEEV. Chickens can get infected but don’t get sick or transmit the disease. Evidence from the chickens revealed that EEEV is present year-round in the Florida Panhandle and that the region could be “seeding” the virus for the rest of Florida and for Northeastern states as well (EEEV is not found west of the Mississippi River). They believe their findings could lead to disease control efforts in the Panhandle that could reduce risks elsewhere in the United States.

See: http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0783

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 19 April 2019

Newly isolated human gut bacterium reveals possible connection to depression


Researchers have established a correlation between depression and a group of neurotransmitter-producing bacteria found in the human gut.
The research team from the U.S. Department of Energy’s (DOE) Argonne National Laboratory, Northeastern University and elsewhere made the connection by first isolating the KLE1738, a bacterium that has a surprising dependency upon a brain chemical called gamma-aminobutyric acid (GABA).
The association of microbial GABAmetabolism with mental health is highly compelling,”
said Jack Gilbert, group leader for microbial ecology at Argonne who also holds new faculty appointments at the University of California, San Diego, in the Department of Pediatrics and at Scripps Institution of Oceanography.
The general ability of the microbiome to produce and/or consume GABA has not been as broadly described before, and a bacterium dependent on GABAhas never been reported.”
Gilbert and 18 co-authors published their findings on December 102018, in Nature Microbiology.
Because of its unique growth requirements, nobody else has reported growing KLE1738,”
said Philip Strandwitz, the article’s lead author and a postdoctoral research associate at Northeastern University’s Antimicrobial Discovery Center. Strandwitz and his colleagues have proposed the name Evtepia gabavorous for KLE1738. They will more fully describe the bacterium in a future publication.


KLE1738 had previously appeared on the ?most wanted list” of the National Institutes of Health, meaning that it had yet to be cultured, despite its relative prevalence in the human gut. The bacterium has been detected in nearly 20 percent of the human gut microbiomes available in the Integrated Microbial Next Generation Sequencing Database.
Gut microbiota, the entire collection of microorganisms found in that habitat, affect many important functions, including the immune response and the nervous system. Nevertheless, many microorganisims residing in the human gut remain uncultured, which the research team called ?an obstacle for understanding their biological roles” in the Nature Microbiologyarticle.
More such microorganisms probably remain uncultured because they require key growth factors that are provided by neighboring bacteria in their natural environments, but not under artificial laboratory conditions. During an extensive screening process, the team found that KLE1738 required the presence of Bacteroides fragilis, a common human gut bacterium, to grow.
Further biological testing and purification led to the isolation of GABA as the growth factor produced by Bacteroides fragilisGABA was, in fact, the only nutrient tested during the experiments that supported the growth of KLE1738.
In the next research phase, the team explored the possible connection between Bacteroides and depression. Stool samples and functional magnetic resonance imaging measurements of brain activity were collected from 23 subjects suffering from clinically diagnosed depression.
The researchers found an inverse relationship between the relative abundance of fecal Bacteroidesand functional connectivity in a part of the brain associated with elevated activity during depression. This means that low abundance of Bacteroides was associated with high activity in that part of the brain, and vice versa.
A good first step is to repeat our findings in additional human cohorts, which we are actively exploring,”
said Strandwitz of further research.
When it comes to depression, animal models are often difficult to translate, which is why we are so excited about human studies. “

Recent work published in the journals Science and Cell have identified the presence of sensory neurons in the gut that are hard-wired to the brain. ?
It would be great to explore whether microbial GABA can act as a signal via that pathway,”
said Anukriti Sharma, a co-author of the Nature Microbiology article and a postdoctoral scholar at Argonne.
Strandwitz and co-author Kim Lewis, a distinguished university professor at Northeastern, have founded a biotechnology company, Holobiome, to develop microbiome-based therapeutics that target diseases of the nervous system. Gilbert is a member of the company’s scientific advisory board. Additional research will be needed, however, before it may become possible to develop a treatment for people suffering from depression.
Significant work must be done to first, validate the link between microbial GABA producers and depression. And second, if validated, identify the right approach to develop bacterial — or some sort of intervention — as therapeutics.”

Strandwitz said.
Source: Microbiome Times

Thursday, 18 April 2019

New disease surveillance tool


A new computational method called 'CATCH' designs molecular 'baits' for any virus known to infect humans and all their known strains, including those that are present in low abundance in clinical samples, such as Zika. The approach can help small sequencing centers around the globe conduct disease surveillance, which is crucial for controlling outbreaks.

Scientists have been able to detect some low-abundance viruses by analyzing all the genetic material in a clinical sample, a technique known as "metagenomic" sequencing, but the approach often misses viral material that gets lost in the abundance of other microbes and the patient's own DNA.
Another approach is to "enrich" clinical samples for a particular virus. To do this, researchers use a kind of genetic "bait" to immobilize the target virus's genetic material, so that other genetic material can be washed away. Scientists in the Sabeti lab had successfully used baits, which are molecular probes made of short strands of RNA or DNA that pair with bits of viral DNA in the sample, to analyze the Ebola and Lassa virus genomes. However, the probes were always directed at a single microbe, meaning they had to know exactly what they were looking for, and they were not designed in a rigorous, efficient way.


What they needed was a computational method for designing probes that could provide a comprehensive view of the diverse microbial content in clinical samples, while enriching for low-abundance microbes like Zika.

Short for "Compact Aggregation of Targets for Comprehensive Hybridization," CATCH allows users to design custom sets of probes to capture genetic material of any combination of microbial species, including viruses or even all forms of all viruses known to infect humans.

To run CATCH truly comprehensively, users can easily input genomes from all forms of all human viruses that have been uploaded to the National Center for Biotechnology Information's GenBank sequence database. The program determines the best set of probes based on what the user wants to recover, whether that's all viruses or only a subset. The list of probe sequences can be sent to one of a few companies that synthesize probes for research. Scientists and clinical researchers looking to detect and study the microbes can then use the probes like fishing hooks to catch desired microbial DNA for sequencing, thereby enriching the samples for the microbe of interest.

Tests of probe sets designed with CATCH showed that after enrichment, viral content made up 18 times more of the sequencing data than before enrichment, allowing the team to assemble genomes that could not be generated from un-enriched samples. They validated the method by examining 30 samples with known content spanning eight viruses. The researchers also showed that samples of Lassa virus from the 2018 Lassa outbreak in Nigeria that proved difficult to sequence without enrichment could be "rescued" by using a set of CATCH-designed probes against all human viruses. In addition, the team was able to improve viral detection in samples with unknown content from patients and mosquitos.

See: Hayden C. Metsky, Katherine J. Siddle, Adrianne Gladden-Young et al. Capturing sequence diversity in metagenomes with comprehensive and scalable probe design. Nature Biotechnology, 2019; 37 (2): 160 DOI: 10.1038/s41587-018-0006-x

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 17 April 2019

New strategy to tackle “don’t eat me” signal on cancer cells


Myeloid immune cells kill cancer cells by eating them but cancer cells prevent this from happening by giving out a 'do not eat me' signal. Led by immunologists Ton Schumacher (Netherlands Cancer Institute and Oncode) and Ferenc Scheeren (Leiden University Medical Center), researchers from various research institutes have discovered a new method to inhibit the 'don’t eat me' signal, and have therefore found a new target for immunotherapy.

On 4 March 2019, the researchers published an article on this topic in the scientific journal Nature Medicine.

The “don’t eat me” signal

Different types of immune cells have different strategies to fight cancer cells. For example, some immune cells—myeloid cells—kill cancer cells by eating them. Cancer cells can prevent this by expressing proteins on their surfaces which give out inhibiting signals to the immune cells. One example is the 'don’t eat me' signal, officially called CD47, which ensures that the cancer cell stays alive.

Researchers around the world are now looking for medicines to block this “don’t eat me” signal. One method for doing so is to intervene on the surface of the cell, by covering the CD47 molecules on cancer cells with a specific antibody.

This method of blocking the CD47 signal from cancer cells is currently being clinically developed and is promising, but there are side effects, such as a decrease in red blood cells. On top of that, patients require a weekly IV to block the CD47 molecules on cancer cells adequately.

Are there any other ways to counteract the “don’t eat me” signal CD47? To investigate this, PhD student Meike Logtenberg, lead author of the article, set up a collaboration with experimental geneticist Thijn Brummelkamp, who uses a unique method to map the genetic regulation of any desired protein in a cell. "With this screening method you can potentially find new targets," says Meike Logtenberg.

Screening the CD47 molecule

Together with the immunologists, Brummelkamp screened CD47, which also plays a role in healthy cells as an immune system check, and found that the QPCTL enzyme is a crucial protein in forming the “don’t eat me” signal. QPCTL changes the structure of the CD47 protein and without any QPCTL activity, the CD47 molecules are no longer able to give off an inhibiting signal to myeloid cells.

Research leader Ton Schumacher: "In collaboration with the groups of Jeanette Leusen (UMC Utrecht) and Timo van den Berg (Sanquin Research), we then showed that as soon as we inhibited the activity of this enzyme, we instantly blocked the “don’t eat me” signal on tumor cells. Identifying this new target is especially relevant because the substances we can use to inhibit the QPCTL enzyme are likely to have some advantages over the strategies currently being clinically developed to inhibit the CD47 signal route."

Blocking the signal

With a QPCTL inhibitor, for example, it becomes easier to control how long you want to block the signal, and so-called small molecule inhibitors are easier to administer than antibodies. Moreover, the substance does not inhibit the CD47 molecules on the healthy red blood cells that a patient receives during a blood transfusion to fight anaemia.

Clinical studies

The researchers expect that QPCTL inhibitors will be available for testing in clinical studies in the coming years. First clinical trials are expected to take place in patients with blood cancer.

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Logtenberg et al., ‘Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRP axisand target for cancer immunotherapy’, Nature Medicine 4 March 2017 doi: 10.1038/s41591-019-0356-z


Corresponding author: Ton Schumacher
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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