Friday, 31 May 2019

New imaging reveals previously unseen vulnerabilities of HIV

Imagine that HIV is a sealed tin can: if you opened it, what would you find inside? An international team led by researchers at the University of Montreal Hospital Research Centre (CRCHUM), Tufts University School of Medicine, and the University of Melbourne think they know. Researchers have visualized what the "open can" of the human immunodeficiency virus looks like, revealing a previously unknown virus shape and a very detailed image of the vulnerabilities of the virus.

The breakthrough was made possible through the use of a molecular "can opener" to expose parts of the virus envelope that can be targeted by antibodies.

The characterization of the new shape of the virus envelope reveals unique details about the vulnerability of HIV that might be useful in strategies aimed at its eradication. This finding opens new paths in the fight against the virus.

When HIV infects cells of the human immune system, it uses its envelope's spike to attach itself to specific receptors on the cells, called CD4 and CCR5. Binding to the CD4 receptor triggers changes in the shape of the envelope that allow the virus to infect the host cell. The new research describes the use of small-molecule CD4-mimetic compounds designed and synthesized at the University of Pennsylvania to force the virus to open up and to expose vulnerable parts of its envelope, allowing the immune system cells to kill the infected cells.

In an earlier study published in PNAS in 2015, researchers led by Finzi showed that exposing these vulnerable parts of the envelope facilitates the elimination of infected cells by a mechanism known as antibody-dependent cellular cytotoxicity (ADCC).

Tufts researchers were able to visualize the previously unknown shape of the virus envelope using a new technology -- single-molecule Förster resonance energy transfer, or smFRET -- that allows researchers to see how distinct elements of the envelope move with respect to one another. This provides a direct means of seeing that the HIV envelope is a dynamic machine with moving parts that allows it to adopt various shapes in response to stimuli such as antibodies or small molecules.

See: An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity. Cell Host & Microbe, 2019; 25 (4): 578 DOI: 10.1016/j.chom.2019.03.002

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 30 May 2019

Harnessing microorganisms for smart microsystems

A research team at the Department of Mechanical Engineering at Toyohashi University of Technology has developed a method to construct a biohybrid system that incorporates Vorticella microorganisms. The method allows movable structures to be formed in a microchannel and combined with Vorticella. In addition, the biohybrid system demonstrates the conversion of motion from linear motion to rotation. .

Complex control systems are required for the operation of smart microsystems, and their sizes should be reduced. Cells are expected to be applicable as alternatives to these complex control systems. Because a cell integrates many functions in its body and responds to its surrounding environment, cells are intelligent and can be used in smart micromechanical systems.

In particular, Vorticella convallaria has a stalk (approximately 100 μm in length) that contracts and relaxes, and it works as an autonomous linear actuator. The combination of stalks and movable structures will form an autonomous microsystem. However, the construction of biohybrid systems in a microchannel is difficult, as it is necessary to establish a cell patterning method and a biocompatible assembly process for the structure and cell.

The research group has developed a method to construct a biohybrid system that incorporates Vorticella. "Harnessing microorganisms requires that a batch assembly method be applied to the movable components in a microchannel. It is necessary to pattern a water-soluble sacrificial layer and confine the movable components in a microchannel," says Moeto Nagai, a lecturer at Toyohashi University of Technology and the leader of the research team. Vorticella cells were placed around blocks in the channel by applying magnetic force. These processes were applied to demonstrate how Vorticella converts the motion of a movable component.

After permeabilized treatment, Vorticella stalks respond to changes in calcium ion concentration, and they can operate as calcium ion-responsive valves. The research team believes that calcium ion-sensitive motors of Vorticella will facilitate the realization of autonomous fluidic valves, regulators, and mixers, as well as wearable smart microsystems, such as an automated insulin infusion pump for diabetes.

See: Moeto Nagai, Kohei Tanizaki, Takayuki Shibata. Batch Assembly of SU-8 Movable Components in Channel Under Mild Conditions for Dynamic Microsystems: Application to Biohybrid Systems. IEEE/ASME Journal of Microelectromechanical Systems, 2019 DOI: 10.1109/JMEMS.2019.2907285
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 29 May 2019

MHRA GXP Data Integrity Guidance

An interesting MHRA blog post has been posted, looking at data integrity from the GCP perspective. The blog is from Paula Walker.

Here is an excerpt:

“The guidance describes the need for a documented audit trail review, where the need for and extent of such evaluation is identified in the trial risk assessment, performed prior to the trial commencing.  This could include evaluation of data points associated with critical/complex trial processes, in other words, where the trial risks are.  This has led many to question whether this means that sponsors, or indeed Clinical Research Organisations (CROs) working on behalf of sponsors, need to develop a generic audit trail review Standard Operating Procedure (SOP) that covers this process, that is, an SOP not specific to a particular clinical trial as part of their quality system. 

To answer this question, we would refer organisations back to the statement that the need for a review of an audit trail should be determined by a risk assessment based on the requirements of the trial, taking into account the systems, procedures and controls in place to be used in the trial.  Therefore, to have a generic SOP would probably not add any benefit to this process and is not mandated by the guidance or expected by GCP inspectors.”

To read the whole blog, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 28 May 2019

Falsified Medicines Directive: Safety Features

The EMA’s safety feature provisions enter into force on 9 February 2019. Member states are required to implement the new falsified medicines safety features for almost all prescription-only medicines which aim to prevent falsified medicinal products from entering the pharmaceutical supply chain. The safety features are placed on the packaging of the respective medicinal products by the pharmaceutical manufacturer and consist of the following:

a unique identifier, in the form of a 2D data matrix barcode, allowing the verification of the authenticity and the identification of an individual pack of a medicinal product
anti-tampering device

 Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 27 May 2019

New EudraVigilance system improves reporting of side effects

The new and improved EudraVigilance, the European system for managing and analysing information on suspected adverse reactions to medicines that are authorised or being studied in clinical trials in the EU, received more than 2 million reports of suspected side effects in 2018. This is an increase of 37% compared to 2017 which largely reflects that from November 2017 the national competent authorities and the marketing authorisation holders were required to report non-serious cases of suspected adverse reactions to EudraVigilance, having previously only reported serious cases.

This was also a key driver for the increase in the number of reports received from European patients and consumers through national authorities and marketing authorisation holders, which almost doubled between 2017 and 2018. Improvements in patient reporting also reflect efforts at national level to encourage patients to share information on side effects through information campaigns. These and other findings are summarised in EMA’s annual report on Eudravigilance.

According to the report, EMA reviewed more than 2,200 potential signals. This is information on a new adverse reaction or new aspect of a known adverse reaction that is potentially caused by a medicine and warrants further investigation. Almost 80% of these signals originated from monitoring the EudraVigilance database. Other signals were generated from clinical studies and scientific literature.

To see the report, go to:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 26 May 2019

Gum bacteria implicated in Alzheimer's disease

Researchers are reporting new findings on how bacteria involved in gum disease can travel throughout the body, exuding toxins connected with Alzheimer's disease, rheumatoid arthritis and aspiration pneumonia. They detected evidence of the bacteria in brain samples from people with Alzheimer's and used mice to show that the bacterium can find its way from the mouth to the brain.

The bacterium, Porphyromonas gingivalis, is the bad actor involved in periodontitis, the most serious form of gum disease. These new findings underscore the importance of good dental hygiene as scientists seek ways to better control this common bacterial infection.

The inference is that people with genetic risk factors that make them susceptible to rheumatoid arthritis or Alzheimer's disease should be extremely concerned with preventing gum disease.

While previous researchers have noted the presence of P. gingivalis in brain samples from Alzheimer's patients, Potempa's team, in collaboration with Cortexyme, Inc., offers the strongest evidence to date that the bacterium may actually contribute to the development of Alzheimer's disease. Potempa will present the research at the American Association of Anatomists annual meeting during the 2019 Experimental Biology meeting, held April 6-9 in Orlando, Fla.

The researchers compared brain samples from deceased people with and without Alzheimer's disease who were roughly the same age when they died. They found P. gingivalis was more common in samples from Alzheimer's patients, evidenced by the bacterium's DNA fingerprint and the presence of its key toxins, known as gingipains.

In studies using mice, they showed P. gingivalis can move from the mouth to the brain and that this migration can be blocked by chemicals that interact with gingipains. An experimental drug that blocks gingipains, known as COR388, is currently in phase 1 clinical trials for Alzheimer's disease. Cortexyme, Inc. and Potempa's team are working on other compounds that block enzymes important to P. gingivalis and other gum bacteria in hopes of interrupting their role in advancing Alzheimer's and other diseases.

The researchers also report evidence on the bacterium's role in the autoimmune disease rheumatoid arthritis, as well as aspiration pneumonia, a lung infection caused by inhaling food or saliva.

P. gingivalis's main toxins, the enzymes the bacterium need to exert its devilish tasks, are good targets for potential new medical interventions to counteract a variety of diseases. The beauty of such approaches in comparison to antibiotics is that such interventions are aimed only at key pathogens, leaving alone good, commensal bacteria, which we need.

P. gingivalis commonly begins to infiltrate the gums during the teenage years. About one in five people under age 30 have low levels of the bacterium in their gums. While it is not harmful in most people, if it grows to large numbers the bacteria provoke the body's immune system to create inflammation, leading to redness, swelling, bleeding and the erosion of gum tissue.

Making matters worse, P. gingivalis even causes benign bacteria in the mouth to change their activities and further increase the immune response. Bacteria can travel from the mouth into the bloodstream through the simple act of chewing or brushing teeth.

The best way to prevent P. gingivalis from growing out of control is by brushing and flossing regularly and visiting a dental hygienist at least once a year, Potempa said. Smokers and older people are at increased risk for infection. Genetic factors are also thought to play a role, but they are not well understood.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 25 May 2019

How microbes in the human body swap genes

Bacteria in the human body are sharing genes with one another at a higher rate than is typically seen in nature, and some of those genes appear to be traveling -- independent of their microbial hosts -- from one part of the body to another.

The findings are the result of a molecular data-mining method initially conceptualized by Kyung Mo Kim, a senior research scientist at the Korea Polar Research Institute. This computationally challenging method allowed them to identify instances of "horizontal gene transfer," the direct transfer of genes between organisms outside of sexual or asexual reproduction. Horizontal gene transfer is a major force of exchange of genetic information on Earth, These exchanges allow microorganisms to adapt and thrive, but they are likely also important for human health. There are some bacteria that cannot live outside our bodies and some without which we cannot live.

For the new analysis, the scientists used genomic information to build tens of thousands of "family trees" of bacteria that colonize the human body. Reconciling those with trees of microbial genes allowed the team to tease out which genes had been inherited and which were the result of horizontal gene transfer.

The researchers studied human-associated microorganisms, since they are known to be key players in maintaining human health and metabolism and calculated gene-transfer rates and direction -- who transferred what to whom -- for more than 1,000 reference bacterial genomes sampled by the National Institutes of Health Human Microbiome Project.

The bacteria had been sampled from six human body sites: the gut, skin, oral cavity, blood, urogenital tract and airways. The researchers found evidence to support earlier findings that human-associated bacteria are quite promiscuous with their genes.

The horizontal exchange between microbes in our bodies is about 30 percent higher than what you'll find on the rest of the planet. This implies that our bodies provide a niche that is unique and facilitates innovation at the microbe level.

About 40 percent of gene swapping occurred among bacteria living in the same body sites. The other 60 percent involved gene sharing among bacteria in different tissues, for example between organisms in the gut and in blood.

In all cases, gene transfer was most common among closely related organisms, regardless of whether they occupied the same or different bodily tissues. In fact, the researchers report, gene sharing among organisms in different body sites occurred at a higher rate than gene sharing among distantly related bacteria living at the same sites.

The researchers say other scientists can use the tool they developed for this work, HGTree, to more accurately predict which genes were inherited "vertically," through the process of reproduction, and which were picked up from other microbes through horizontal gene transfer. This will lead to an improved understanding of microbial -- and human -- evolution.

See: Hyeonsoo Jeong, Bushra Arif, Gustavo Caetano-Anollés, Kyung Mo Kim, Arshan Nasir. Horizontal gene transfer in human-associated microorganisms inferred by phylogenetic reconstruction and reconciliation. Scientific Reports, 2019; 9 (1) DOI: 10.1038/s41598-019-42227-5

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 24 May 2019

New ‘interspecies communication’ strategy between gut bacteria and mammalian hosts

Bacteria in the gut do far more than help digest food in the stomachs of their hosts, they can also tell the genes in their mammalian hosts what to do.

A study published today in Cell describes a form of “interspecies communication” in which bacteria secrete a specific molecule–nitric oxide–that allows them to communicate with and control their hosts’ DNA, and suggests that the conversation between the two may broadly influence human health.

The researchers out of Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, and Harvard Medical School tracked nitric oxide secreted by gut bacteria inside tiny worms (C. elegans, a common mammalian laboratory model). Nitric oxide secreted by gut bacteria attached to thousands of host proteins, completely changing a worm’s ability to regulate its own gene expression.

The study is the first to show gut bacteria can tap into nitric oxide networks ubiquitous in mammals, including humans. Nitric oxide attaches to human proteins in a carefully regulated manner–a process known as S-nitrosylation–and disruptions are broadly implicated in diseases such as Alzheimer’s, Parkinson’s, asthma, diabetes, heart disease, and cancer.

The findings suggest nitric oxide is a general mechanism by which gut bacteria can communicate with mammalian hosts. Previous work to untangle communication lines to and from gut bacteria has primarily focused on rare molecules that bacteria secrete. The new findings are akin to uncovering a chemical language common across species, as opposed to single words, said senior author Jonathan Stamler, MD, director of the Institute for Transformative Molecular Medicine at Case Western Reserve University School of Medicine and president of the Harrington Discovery Institute at University Hospitals Cleveland Medical Center.

“There is tremendous complexity in the gut, and many researchers are after the next unusual substance produced by a bacterium that might affect human health,”

he says. With trillions of bacteria in the average gut, Stamler decided to look for a common language that all bacterial species might use.

“The enormity of the gut bacteria population and its relationship to the host predicts there will be general means to communicate that we humans can recognize.”

The researchers demonstrated the phenomenon by feeding developing worms bacteria that produce nitric oxide. They then selected one very important protein–argonaute protein, or ALG-1–that is highly conserved from worms to humans and silences unnecessary genes, including genes critical for development. When nitric oxide secreted by the bacteria attached to ALG-1, they developed malformed reproductive organs and died. Too much nitric oxide from bacteria commanded the worms’ DNA silencing proteins and impaired healthy development.

“Practically, animals will not let this happen,”

Stamler said. Instead, the authors speculate a mammalian host outside of a laboratory setting will adjust to accommodate changing nitric oxide levels. Said Stamler,

“The worm is going to be able to stop eating the bacteria that make the nitric oxide, or it will begin to eat different bacteria that makes less nitric oxide, or change its environment, or countless other adaptations. But by the same token, too much nitric oxide produced by our microbiome may cause disease or developmental problems in the fetus.”

The study adds to a growing body of evidence that bacteria living in the gut, determined by diet and environment, have a tremendous influence on mammalian health. Stamler imagines nitric oxide may represent an opportunity to manipulate this symbiotic relationship. Just as probiotics are designed to improve digestion, inoculating a person’s gut with bacteria to improve nitric oxide signaling is conceivable.

“I now think of this therapeutically, as a drug. There are tremendous opportunities to manipulate nitric oxide to improve human health.”

While nitric oxide and S-nitrosylation may be a general mode of interspecies communication with broad health implications, it will require additional future research. Will nitric oxide be the only chemical communication channel?

“We’re basically seeing a new field opening for general strategies of communication. There will be others.”


Stamler collaborated with several researchers from Case Western Reserve University School of Medicine on the new study, including first authors Puneet Seth, MD and Paishiun (Nelson) Hsieh, MD, PhD; Suhib Jamal; Liwen Wang, PhD; Mukesh Jain, MD; and Jeff Coller, PhD.

This research was supported in part by grants from the National Institutes of Health (R01-GM099921 to J.S.S., T32GM007250 and F30AG054237 to P.N.H, and R35HL135789 to M.J.).
Puneet, S., et al. “Regulation of microRNA machinery and development by interspecies s-nitrosylation.” Cell. DOI: 10.1016/j.cell.2019.01.037

Source: Microbiome Times

Thursday, 23 May 2019

FDA - Nonproprietary Naming of Biological Products

The FDA has issued a new draft guidance document – “Nonproprietary Naming of Biological Products:  Update”.

This draft guidance describes FDA’s current thinking on nonproprietary names of biological products licensed under section 351 of the Public Health Service Act (PHS Act) that do not include an FDA-designated suffix.  Specifically, the nonproprietary names of these products need not be revised in order to accomplish the objectives of the naming convention described in the Guidance for Industry: Nonproprietary Naming of Biological Products (Naming Guidance). 

Similarly, FDA does not intend to apply the naming convention described in the Naming Guidance to biological products that are the subject of an approved application under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) as of March 23, 2020, when such an application is deemed to be a biologics license application (BLA) under section 351 of the PHS Act on March 23, 2020 (transition biological products).

In addition, this draft guidance describes FDA’s current thinking on the appropriate suffix format for the proper name of an interchangeable biological product licensed under section 351(k) of the PHS Act. For each interchangeable product, FDA intends to designate  a proper name that is 30 a combination of the core name and a distinguishing suffix that is devoid of meaning and 31 composed of four lowercase letters.

FDA is also reconsidering whether vaccines should be within the scope of the naming convention.

To access the document, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 22 May 2019

Oral bacteria 'battle royale' helps explain how a pathogen causes hospital infections

Hundreds of different bacterial species are living inside your mouth. Some are highly abundant, while others are scarce. A few of these oral bacteria are known pathogens. Others are benign, or even beneficial.

Scientists know the genetic makeup of about 70 percent of oral bacteria. What they don't know is which species would live the longest without nutrients in a "battle royale" -- so they decided to find out. The results help explain how certain dangerous bacteria are able to persist in a sterile hospital environment and infect patients.

Researchers from the Forsyth Institute, the J. Craig Venter Institute, the University of Washington, and the University of California, Los Angeles, have described their discovery that three closely related species of bacteria belonging to the family Enterobacteriaceae outlived all other oral bacteria in long-term starvation or "doomsday" experiment.

To create a battle of bacteria, researchers placed hundreds of samples of oral bacteria from human saliva into test tubes. The bacteria, which are accustomed to living in the nutrient-rich mouth, were starved in their new environment. Each day, scientists checked the samples to see which bacteria were still alive.

Nearly every bacterial species died within the first couple of days. But three species -- Klebsiella pneumoniae, Klebsiella oxytoca, and Providencia alcalifaciens -- survived the longest, with Klebsiella pneumoniae and Klebsiella oxytoca surviving for more than 100 days.

Researchers were surprised to find that Klebsiella were among the champions of this bacterial combat. In their natural environment of the oral cavity, Klebsiella are considered an underdog. They account for only about 0.1 percent of all microbes in the mouth. But in an extreme environment deprived of all nutrients, Klebsiella reigned supreme while the bugs normally found in high abundance rapidly died off.

Scientists describe Klebsiella species as opportunistic pathogens. In healthy people, they live in the mouth peacefully, crowded by other microbes and unable to grow or cause trouble. But outside the mouth, where few other bacteria survive, Klebsiella is king. They persist on hospital surfaces, like sinks or tables. If a patient with a compromised immune system makes contact with Klebsiella, that patient could develop an infection.

Infections by Klebsiella can result in a number of dangerous conditions including pneumonia and meningitis. One of the reasons Klebsiella infections are so dangerous is that Klebsiella are particularly adept at developing resistance to antibiotics, as well as transferring this drug resistance to neighboring bacteria.

The finding that these Klebsiella species survive longer than their more benign neighbors in mixtures of saliva is likely to have a great deal of clinical significance, as multiple virulent outbreaks of antibiotic-resistant Klebsiella have been traced back to hospital sinks and drains. This research also helps illuminate a key ecological dynamic of bacterial communities.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 21 May 2019

20 years of sampling and testing programme for medicines

EMA and the European Directorate for the Quality of Medicines & Healthcare (EDQM) have reviewed EMA’s sampling and testing programme for centrally authorised medicines on the EU/EEA market, which has been organised yearly since 1998.

The number of centrally authorised medicines tested every year has steadily increased from nine in the 1997-1998 pilot project to 58 in 2017, totalling over 700 products. Most of the issues identified during the testing resulted in EMA requiring companies to amend the registered manufacturer’s control methods for their medicines. In a small number of cases, the tested samples were not compliant with the authorised quality specifications for the medicine and required other regulatory actions such as re-testing, inspections, recalls or suspension of supply. These are some of the key findings in a report summarising the sampling and testing activities and main achievements over the past 20 years.

The programme is an important part of the supervision of the quality of centrally authorised products (CAPs) for human and veterinary use in all parts of the distribution chain. The tests are aimed at verifying the compliance of medicines with their authorised specifications and ensuring that the manufacturer’s control methods are satisfactory.

To access the report, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 20 May 2019

Bacterial factories to manufacture high-performance proteins for space missions

Scientists report on a new method that takes advantage of engineered bacteria to produce spider silk and other difficult-to-make proteins that could be useful during future space missions.

If produced in sufficient quantities, spider silk could be used for a variety of applications, ranging from bullet-proof fabric to surgical sutures. But spider silk isn't easy to farm -- spiders produce tiny quantities, and some species turn cannibalistic when kept in groups. Therefore, scientists have tried engineering bacteria, yeast, plants and even goats to produce spider silk, but they haven't yet been able to fully replicate the natural fiber's mechanical properties.

Part of the problem is that spider silk proteins are encoded by very long, highly repetitive sequences of DNA. Spiders have evolved ways to keep these sequences in their genome. But when scientists put this type of DNA into other organisms, the genes are very unstable, often getting snipped or otherwise altered by the host's cellular machinery. Zhang and colleagues at Washington University in St. Louis wondered if they could break the long, repetitive sequences into shorter blocks that bacteria could handle and make into proteins. Then, the researchers could assemble the shorter proteins into the longer spider silk fiber.

READ MORE: ISS is not causing bacteria to mutate into dangerous, antibiotic-resistant superbugs

The team introduced genes to bacteria that encoded two pieces of the spider silk protein, each flanked by a sequence called a split intein. Split inteins are naturally occurring protein sequences with enzymatic activity: Two split inteins on different protein fragments can join and then cut themselves out to yield an intact protein. After introducing the genes, the researchers broke open the bacteria and purified the short pieces of spider silk protein. Mixing the fragments caused them to join together through the "glue" of the split intein sequence, which then cut itself out to yield the full-length protein. When spun into fibers, the microbially produced spider silk had all of the properties of natural spider silk, including exceptional strength, toughness and stretchability. The researchers obtained more silk with this method than they could from spiders (as much as two grams of silk per liter of bacterial culture), and they are currently trying to increase the yield even more.

The researchers can make various repetitive proteins simply by swapping out the spider silk DNA and putting other sequences into bacteria. For example, the researchers used the technique to make a protein from mussels that adheres strongly to surfaces. The protein could someday be applied as an underwater adhesive. Now, the researchers are working on streamlining the process so that the protein-joining reaction can occur inside bacterial cells. This would improve the efficiency and potential automation of the system because researchers wouldn't have to purify the two pieces of the protein and then incubate them together.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 19 May 2019

Fast-changing genetics key to hospital superbug survival

A highly drug-resistant bacteria common in hospitals, Klebsiella pneumoniae, represents a significant antimicrobial resistance threat and should be monitored globally, say researchers. The warning follows new genetic analyses revealing how K. pneumoniae are able to quickly evolve to change their genetic makeup. This has implications for understanding how several species of bacteria -- called Enterobacteriaceae -- can rapidly adapt to essentially any antibiotic currently used in treatment.

By genetically analysing 100 strains of K. pneumoniae bacteria sampled from infected patients, carriers without symptoms and the hospital ward environment over a 14-month period, they found that the bacteria were highly transmissible and able to genetically adapt to any available antibiotic within very short periods of time.

The hospital outbreak strains of K. pneumoniae were found to be very highly drug-resistant, with all isolates analysed showing resistance to multiple drug classes, including to Carbapenems -- antibiotics used as a last resort in the treatment of severe infections.

With the number of deaths from drug-resistant infections predicted to rise from 700,000 to 10 million per year by 2050, Carbapenem-resistant Enterobacteriaceae are listed as one of three urgent threats by the Centers for Disease Control and Prevention and a key global 'critical-priority' by the World Health Organization.

READ MORE: Potential antibody treatment for multidrug-resistant K. pneumoniae

The team used whole genome DNA sequence data to reconstruct the evolution of the highly drug-resistant bacteria, including tracking their transmission within the hospital, spanning three campuses, 19 wards and two intensive care units. By using genome-wide genetic data the researchers could clearly follow their spread around the hospital. It's remarkable to see how easily these bacteria were moving between patients, particularly those in intensive care units, but we also found that they were transmitting across different hospital sites via ward equipment, including ward bed rails and medical devices.

The researchers found the bacteria were carrying many resistance plasmids, and in some cases these plasmids were present in multiple copies. We demonstrated that the number of copies helped to predict how successfully treatment was evaded by the bacteria. This means it isn't just the presence of a gene conferring resistance that is important, but also its abundance in an infecting strain.

Journal reference:

Lucy van Dorp, Qi Wang, Liam P. Shaw, Mislav Acman, Ola B. Brynildsrud, Vegard Eldholm, Ruobing Wang, Hua Gao, Yuyao Yin, Hongbin Chen, Chuling Ding, Rhys A. Farrer, Xavier Didelot, Francois Balloux, Hui Wang. Rapid phenotypic evolution in multidrug-resistant Klebsiella pneumoniae hospital outbreak strains. Microbial Genomics, 2019; DOI: 10.1099/mgen.0.000263
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 18 May 2019

Global microbial signatures for colorectal cancer

Patients with colorectal cancer have the same consistent changes in the gut bacteria across continents, cultures, and diets -- a team of international researchers find in a new study. The hope is the results in the future can be used to develop a new method of diagnosing colorectal cancer. This is based on research from the University of Copenhagen The Faculty of Health and Medical Sciences.

Cancers have long been known to arise due to environmental exposures such as unhealthy diet or smoking. Lately, the microbes living in and on our body have entered the stage as key players. But the role that gut microbes play in the development of colorectal cancer -- the third most common cancer worldwide -- is unclear. To determine their influence, association studies have aimed to map how the microbes colonizing the gut of colorectal cancer patients are different from those that inhabit healthy subjects.

Now, researchers have analysed multiple existing microbiome association studies of colorectal cancer together with newly generated data. Their meta-analyses establish disease-specific microbiome changes, which are globally robust -- consistent across seven countries on three continents -- despite differences in environment, diet and life style.

READ MORE: Killer immune cells that halt malaria could hold key to new vaccines

The study led by UCPH and EMBL scientists focuses on a process in which certain gut bacteria turn bile acids that are part of our digestive juices into metabolites that can be carcinogenic. A related study from the University of Trento shows how certain classes of bacteria degrade choline, an essential nutrient contained in meat and other foods, and turn it into a potentially dangerous metabolite. This metabolite has previously been shown to increase cardiovascular disease risk, and can now also be linked to colorectal cancer.

One of the challenges of metagenomic studies, which are based on genetic material from microbes in environmental samples such as stool, is to link genetic fragments to the various microbial organisms they belong to. The goal of this so-called taxonomic profiling task is to identify and quantify the bacterial species present in the sample.

The role of gut microbes in colorectal cancer still needs to be established. If the changes in the microbiome play a role in developing the cancer, they could also be a therapeutic target. Therefore, Manimozhiyan Arumugam hopes that there will be more focus on the role of microbiome in diseases and that researchers will recognize the advantages of collecting microbiome samples, for example, in large cohorts.

Journal reference:

Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nature Medicine, 2019; DOI: 10.1038/s41591-019-0406-6
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 17 May 2019

Tackling challenge of antifungal resistance

New work is helping develop a better understanding of the growing threat posed by antifungal drug resistance. Invasive aspergillosis is a devastating disease caused by breathing in small airborne spores of the fungus Aspergillus fumigatus and it is a condition where drug resistance has been encountered. They have just released a paper revealing how they have been able to identify a previously uncharacterized genetic mutation in clinical isolates that leads to resistance.

Invasive aspergillosis is a devastating disease caused by breathing in small airborne spores of the fungus Aspergillus fumigatus and it is a condition where drug resistance has been encountered.

In a healthy person these spores are destroyed by the body's immune system but in those with a weakened immune system -- such as following organ transplantation or in someone with a lung condition such as asthma or cystic fibrosis -- they can trigger a range of problems including infections.

READ MORE: Fungal spore 'death clouds' key in gypsy moth fight

Every year aspergillosis leads to more than 200,000 life-threatening infections and increasingly resistance to vital antifungal drug treatments makes those infections harder to treat.

National Institutes of Health (USA) funding supported a collaboration between the University of Tennessee, the University of Texas and Swansea University as part of a $2 million, five-year research programme. This support enabled investigation of resistance to the triazole class of antifungal drugs used for treating the disease

A new paper shows how researchers have been able to identify a previously uncharacterised genetic mutation in clinical isolates that leads to resistance.

Journal reference:

Jeffrey M. Rybak, Wenbo Ge, Nathan P. Wiederhold, Josie E. Parker, Steven L. Kelly, P. David Rogers, Jarrod R. Fortwendel. Mutations in hmg1, Challenging the Paradigm of Clinical Triazole Resistance in Aspergillus fumigatus. mBio, 2019; 10 (2) DOI: 10.1128/mBio.00437-19
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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