Tue, 02/24/2015 - 12:31pmCorin Campbell, Univ. of Edinburgh A chemical found in garlic can kill bacteria that cause life-threatening lung infections in people with cystic fibrosis, research suggests. The study is the first to show that the chemical, known as allicin, could be an effective treatment against a group of infectious bacteria that is highly resistant to most antibiotics. Allicin is produced naturally by garlic bulbs to ward off a closely related group of plant pathogens found in soil and water habitats. In the 1980s, the bacteria—known as the Burkholderia cepacia complex (Bcc)—emerged as a cause of serious and transmissible lung infections in people with cystic fibrosis. Measures to limit the spread of Bcc infections among people with cystic fibrosis have brought the number of cases down considerably. However, current therapies available to treat infections—that are potentially fatal—are limited and require the use of combinations of three to four antibiotics at a time. Researchers found that allicin—which can be extracted by crushing raw garlic—inhibits the growth of bacteria and, at higher doses, kills the plant pathogens. The team suggests that allicin kills Bcc bacteria by chemically modifying key enzymes. This deactivates them and halts important biological processes within the pathogens' cells. The team believes allicin-containing remedies could be used in combination with existing antibiotics to treat Bcc infections. However, the researchers say it is important to pinpoint the mechanisms by which allicin kills the bacteria before the chemical can be incorporated into new treatments. The Bcc are highly versatile plant and human pathogens that have not been studied to the same extent as other superbugs—such as MRSA—the team says. The bacteria produce potent antimicrobial agents which kill bacteria and fungi, making them naturally drug-resistant and allowing them to survive in polluted and antibiotic-rich environments. The team says the Bcc also have a range of potential uses in the agriculture industry. The study, published in PLoS One, was funded by the Univ. of Edinburgh and the Biotechnology and Biological Sciences Research Council. Prof. John Govan, of the Univ. of Edinburgh's Centre for Infectious Diseases, who co-led the study, said: "At a time when novel antimicrobial agents are urgently required, chemical and microbiological research has the potential to unlock the rich reservoir of antimicrobial compounds present in plants such as garlic. Allicin-containing compounds merit further investigation as adjuncts to existing treatments for infections caused by Bcc." Dr. Dominic Campopiano, of the Univ. of Edinburgh's School of Chemistry, said: "The medicinal power of garlic has a rich history that dates back thousands of years but the chemical structure of allicin was only revealed in the 1940s. Our work suggests that modern methods should be used to further expand our knowledge of this enigmatic molecule and rejuvenate its potential applications." Source: Univ. of Edinburgh |
sexta-feira, 27 de fevereiro de 2015
Garlic extract could help cystic fibrosis patients fight infection
sábado, 18 de outubro de 2014
Cystic Fibrosis lung infection: Scientists open black box on bacterial growth
Researchers from the University of Copenhagen have shown for the first time how bacteria can grow directly in the lungs of Cystic fibrosis patients, giving them the opportunity to get tremendous insights into bacteria behavior and growth in chronic infections.
The study also discovered the bacterial growth in chronic lung infections among cystic fibrosis (CF) patients was halted or slowed down by the immune cells. The researchers discovered the immune cells consumed all the oxygen and helped "suffocate" the bacteria, forcing the bacteria to switch to a much slower growth.
The findings have recently been published in the journal Infection and Immunity, ASM, USA.
Professor Thomas Bjarnsholt and Ph.D. student Kasper Nørskov Kragh from the Department of International Health, Immunology and Microbiology were able to measure the growth of bacteria directly in transplanted infected tissue without disturbing the bacterial cells, giving them the opportunity to get tremendous insights into bacteria behavior and growth in chronic infections.
"The "suffocating" mechanism of the immune cells is the first time a bacteriostatic effect of immune cells has been described. The immune cells have up until now thought to only kill bacteria not halt their growth. In addition this helps us explain why the intensive and combinatory drug treatment approach developed and used in the CF clinic at Rigshospitalet, Copenhagen is as successful as it is," says Professor Bjarnsholt.
Better treatment
The growth of bacteria in chronic infection is poorly understood and up until now it has been impossible to open up the black box. This is all the more paradoxical as the effect of antibiotics are very closely connected to the rate of growth of the target bacteria. Most types of antibiotic are ineffective against dormant bacterial cells yet this study finally opens up the black box and helps pinpoint the best treatment of chronic lung infection among cystic fibrosis patients. Being able to understand bacterial growth will in the future enable clinicians to improve treatment with known antibiotics, combinations or give raise to new targets in antibiotic development.
"When we applied this to measure growth for bacteria living in biofilm in explanted lunge tissue, we saw a diverse pattern of growth throughout our tissue sample. This puzzled us, and so we investigated possible correlations, and found that high local concentrations of immune cells restricted the growth of the bacteria. Furthermore in vitro experiments supported this mechanism of how the immune cells can remove oxygen and in this way vigorously restrict the bacterial growth," adds Kasper Nørskov Kragh.
On the right track
The main goal of the project was to improve the understanding of the bacterial behavior in chronic infections including CF, and how the bacteria and immune defense compete with each other.
"We show that it is possible to study the bacteria not only in shake flasks in the laboratory but directly in the very complex environment in an infection. This is a major improvement for chronic infections in general. On top of this, the new mechanism of the white blood cells is very important to understand chronic infections. It is fair to say that we are on the right track to understand chronic infections like cystic fibrosis and piece by piece we will solve the puzzle," concludes Professor Bjarnsholt.
Story Source:
The above story is based on materials provided by University of Copenhagen – The Faculty of Health and Medical Sciences. Note: Materials may be edited for content and length.
Journal Reference:
- K. N. Kragh, M. Alhede, P. O. Jensen, C. Moser, T. Scheike, C. S. Jacobsen, S. Seier Poulsen, S. R. Eickhardt-Sorensen, H. Trostrup, L. Christoffersen, H.-P. Hougen, L. F. Rickelt, M. Kuhl, N. Hoiby, T. Bjarnsholt. Polymorphonuclear Leukocytes Restrict Growth of Pseudomonas aeruginosa in the Lungs of Cystic Fibrosis Patients. Infection and Immunity, 2014; 82 (11): 4477 DOI: 10.1128/IAI.01969-14
Story Source:
The above story is based on materials provided by University of Copenhagen – The Faculty of Health and Medical Sciences. Note: Materials may be edited for content and length.
Journal Reference:
- K. N. Kragh, M. Alhede, P. O. Jensen, C. Moser, T. Scheike, C. S. Jacobsen, S. Seier Poulsen, S. R. Eickhardt-Sorensen, H. Trostrup, L. Christoffersen, H.-P. Hougen, L. F. Rickelt, M. Kuhl, N. Hoiby, T. Bjarnsholt. Polymorphonuclear Leukocytes Restrict Growth of Pseudomonas aeruginosa in the Lungs of Cystic Fibrosis Patients. Infection and Immunity, 2014; 82 (11): 4477 DOI: 10.1128/IAI.01969-14
University of Copenhagen – The Faculty of Health and Medical Sciences. "Cystic Fibrosis lung infection: Scientists open black box on bacterial growth." ScienceDaily. ScienceDaily, 17 October 2014. <www.sciencedaily.com/releases/2014/10/141017093120.htm>.
quinta-feira, 16 de outubro de 2014
Potential drug could ease impact of bacterial lung infections in cystic fibrosis patients, tests suggest
October 14, 2014
By screening over 2,000 approved drugs and natural products, scientists have shown that tannic acid may help ease the impact of bacterial lung infections in cystic fibrosis patients. Tests completed using experimentally modified frog oocytes show that tannic acid counteracts the harmful effect of an enzyme produced by the bacterium Staphylococcus aureus (S. aureus). However, more research is needed to find out if tannic acid can help treat S. aureus infections in humans.
By screening over 2,000 approved drugs and natural products, scientists have shown that tannic acid may help ease the impact of bacterial lung infections in cystic fibrosis patients. Tests completed using experimentally modified frog oocytes show that tannic acid counteracts the harmful effect of an enzyme produced by the bacterium Staphylococcus aureus (S. aureus). However, more research is needed to find out if tannic acid can help treat S. aureus infections in humans.
From an early age, the lungs of individuals with cystic fibrosis (CF) are colonised and infected by bacteria, a common example being S. aureus. These bacterial infections cause the lungs to become inflamed, infected, and can eventually lead to permanent lung damage. Researchers from the University of Pennsylvania and the Howard Hughes Medical Institute previously showed that an enzyme called Sphingomyelin phosphodiesterase C (SMaseC) produced by the S. aureus bacterium may harm the health of CF patients. Now, they have discovered an inhibitor for this pathogenic bacterial enzyme.
In patients suffering from CF, the cystic fibrosis "transmembrane conductance regulator" (CFTR) channels are faulty, causing a thick mucus to build up in their lungs. In these experiments, the authors used oocytes from the Xenopus type of frog -- that had been genetically modified to express CFTR channels on their cell surface -- to measure the effect that SMaseC has on CFTR channels. They saw that the SMaseC enzyme suppresses CFTR channel activity in these experimentally modified frog oocytes, and also in a human lung cell line.
These results suggest that the SMaseC enzyme, produced by the S. aureas bacterium, may reduce any residual channel activity in CF patients. The problems originating from genetic defects in CFTR channels are likely made greater if the enzyme reduces the function of the CFTR channel even further.
SMaseC also suppresses a type of voltage-gated potassium channel, known as the Kv1.3 channel, in immune cells. Suppression of these potassium channels is known to weaken host immunity, which would make it more difficult for the CF patients to recover from lung infections.
To try and counteract the effects of the enzyme, the researchers went on to test a collection of approved drugs and natural products in a chemical library. They found that tannic acid -- a readily available and inexpensive natural product that has been used to treat disease as far back as 1850 -- stopped SMaseC from having a negative effect on both the CFTR and the Kv1.3 channels. "We hope to test whether the application of the SMaseC inhibitor tannic acid, in conjunction with effective antibiotic treatment and supportive measures, will provide a significant therapeutic improvement over current treatments for cystic fibrosis," Dr. Zhe Lu, the senior author, says. His team is also working hard to understand the exact mechanism by which tannic acid counters the negative actions of SMaseC.
Story Source:
The above story is based on materials provided by eLife. Note: Materials may be edited for content and length.
Journal Reference:
- Yajamana Ramu, Yanping Xu, Hyeon-Gyu Shin, Zhe Lu. Counteracting suppression of CFTR and voltage-gated K channels by a bacterial pathogenic factor with the natural product tannic acid. eLife, 2014; 3 DOI: 10.7554/eLife.03683
domingo, 28 de setembro de 2014
Antibacterial resistance a cause for major concern, cystic fibrosis experts say
World-leading cystic fibrosis experts, from Queen's University Belfast, have called for greater research to address the major concern of antibacterial resistance.
Professor Stuart Elborn, an international authority on respiratory medicine, said that more funding and further research are required into antibiotic resistance in order to improve patient outcomes for people with Cystic Fibrosis.
In his paper, Infections in chronic lung diseases 2, which was recently published in The Lancet, Professor Elborn reviews current research into infections in chronic lung diseases. Professor Elborn and his colleagues state that while not all resistance found in bacteria is caused by antibiotics, the increasing resistance to antibiotics is proving a major problem in treating people with Cystic Fibrosis.
Speaking about his research Professor Elborn, Dean of the School of Medicine, Dentistry and Biomedical Sciences at Queen's, said: "Our review of current research has found a need for further investigation into antibacterial resistance. While antibiotic treatment has undeniably resulted in increased life expectancy for patients with Cystic Fibrosis during the past 50 years, the emergence of antimicrobial resistance is a cause for major concern.
"We need more research into how to improve cystic fibrosis patient outcomes while reducing antibiotic resistance. We need to look at the use of compounds that may work against bacteria in a way that helps our current antibiotics to be more effective. Such compounds are readily available for treatment of other conditions. At Queen's we are leading the way and are working on developing some of these compounds.
Story Source:
The above story is based on materials provided by Queen's University, Belfast. Note: Materials may be edited for content and length.
Journal Reference:
- Laura J Sherrard, Michael M Tunney, J Stuart Elborn. Antimicrobial resistance in the respiratory microbiota of people with cystic fibrosis. The Lancet, 2014; 384 (9944): 703 DOI: 10.1016/S0140-6736(14)61137-5
terça-feira, 3 de junho de 2014
Increased mucins pinned to worsening cystic fibrosis symptoms
The research, published in the Journal of Clinical Investigation, shows that a three-fold increase of mucins dramatically increases the water-draining power of the mucus layer. This hinders mucus clearance in the CF lung, resulting in infection, inflammation, and ultimately lung failure.
"Our finding suggests that diluting the concentration of mucins in CF mucus is a key to better treatments," said Mehmet Kesimer, PhD, associate professor of pathology and laboratory medicine and co-senior author of the JCI paper.
Ashley Henderson, MD, assistant professor of medicine and co-first author of the JCI paper, added, "We think this study shows why nebulized hypertonic saline [sterile salty water] improves the hydration of the CF airway, improves the patient's mucus clearance and, in so doing, increases lung function."
The UNC study also casts further doubt on a controversial 2004 study that disputed the theory that mucins play a major role in CF.
This work, a collaboration of 13 UNC scientists, is part of an extensive UNC lung research program based in the new Marsico Lung Institute, which is led by Richard Boucher, MD, co-senior author of the JCI study.
"This paper points to a therapeutic strategy to rectify this problem of mucus clearance and provides signposts, or biomarkers, to guide development of novel therapies," said Boucher, the James C. Moeser Eminent Distinguished Professor of Medicine. Also, by measuring mucin concentration in patient mucus, doctors could learn whether therapies are working and to what degree.
Scientists and doctors have known for a long time that failing to clear mucus is the major reason why CF patients face chronic lung infection and inflammation. But the mechanisms of this failure have not been well understood.
Normally, when we breathe, the mucosal layer of our lungs trap the contaminants -- dust, pollutants, bacteria -- naturally found in air. Then, epithelial cells with hair-like cilia brush the mucus up and out of our lungs. In people with cystic fibrosis, though, this process doesn't work as well because they lack a properly functioning CFTR gene. They continually battle infections and must work hard to clear mucus from their lungs.
This is where mucins come into play. Mucins give mucus its gel-like thickness and elasticity. "Without mucins, mucus would have the viscosity of blood," Kesimer said. "The vast majority of mucus is water, but 30 to 35 percent of the remaining solid material is made up of mucins. They form a network of bonds that serves as a framework."
This is why Kesimer and his UNC mentor, the late John Sheehan, PhD, Distinguished Professor of Biochemistry and Biophysics, suspected that something must happen to mucins in the CF lung. They and others knew that CF mucus is typically drier than normal mucus.
Back in 2004, however, other researchers used a standard immunologic analysis to show that mucins were decreased in CF secretions. They suspected DNA was the main culprit that caused problems in CF mucus. Sheehan and Kesimer were skeptical, as was Henderson, a clinician who saw CF patients and had been a research fellow in Sheehan's lab. They set out to conduct various novel experiments to physically measure the amount of mucins in CF secretions and normal mucus.
In one experiment, they used a technique called size exclusion chromatography: in a column, they added custom-made beads that had small pores. Smaller proteins could enter the pores while mucins could not. Through this separation, Kesimer and Henderson's team isolated the mucins and simultaneously measured their concentration using a refractometer.
By using sputum samples from CF patients, the researchers found that CF mucus contained three times as many mucins than did normal samples. They also conducted experiments to show that mucin overabundance led to a six-fold increase of the pressure between the mucus layer and the ciliated layer.
This finding affirms the CF disease model that UNC researchers published in the journal Science in 2012. In essence, in a CF patient, the increased osmotic pressure of the concentrated mucus layer crushes the ciliated cells so that mucus is not cleared. The lung becomes a breeding ground for bacteria. This leads to more mucins, more mucus, inflammation, and subsequently lung failure.
Moreover, Kesimer's team showed precisely why the 2004 research was flawed. Those researchers used a classic antibody based immunologic technique called a western blot, which measures the expression of a given protein -- in this case mucins -- based on an antibody response to that protein.
But, as Kesimer pointed out, antibodies must latch onto proteins at specific sites on the proteins' surfaces. When Kesimer conducted the western blot, he got the same result as the 2004 researchers. But then he used a technique called mass spectrometry to find that CF secretions are full of proteases -- enzymes that break down molecules. The mass spectrometry showed that the proteases degraded the mucins, essentially "erasing" many of the sites where antibodies could bind without disrupting the structural integrity of mucins.
"For that reason, we saw less antibody response using the western blot," Kesimer said. And so it looked as if there were fewer mucins. "But by using more accurate methods, we clearly saw the increase of mucins. In fact, we've analyzed many samples of sputum from patients with other chronic pulmonary diseases and we saw the increase in mucins in them, as well."