NTU researchers make breakthrough to tackle growing concern of antibiotic resistance

Scientists at Nanyang Technological University, Singapore (NTU Singapore) have discovered that antibiotics can continue to be effective if bacteria's cell-to-cell communication and ability to latch on to each other are disrupted.

This research breakthrough is a major step forward in tackling the growing concern of antibiotic resistance, opening up new treatment options for doctors to help patients fight against chronic and persistent bacterial infections.

The study, led by Assistant Professor Yang Liang from the Singapore Centre for Environmental Life Sciences (SCELSE) at NTU, found that a community of bacteria, known as biofilm, can put up a strong line of defence to resist antibiotics. The NTU team has successfully demonstrated how biofilms can be disrupted to let antibiotics continue their good work.

The research was published recently in Nature Communications, a prestigious academic journal by the Nature Publishing Group.

"Many types of bacteria that used to be easily killed by antibiotics have started to develop antibiotic resistance or tolerance, either through acquiring the antibiotic resistant genes or by forming biofilms," said Asst Prof Yang, who also teaches at NTU's School of Biological Sciences.

"The US Center for Disease Control estimates that over 60 per cent of all bacterial infections are related to biofilms. Our study has shown that by disrupting the cell-to-cell communication between bacteria and their ability to latch on to each other, we can compromise the biofilms, leaving the bacteria vulnerable and easily killed by antibiotics."

Bacterial resistance to antibiotics is rapidly growing world-wide and this puts at risk the ability to treat common infections in the community and hospitals.

The World Health Organisation states on its factsheet on Antimicrobial resistance that  "without urgent, coordinated action, the world is heading towards a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill".

Associate Professor Kevin Pethe, an expert in antibiotic development and infectious diseases from NTU's Lee Kong Chian School of Medicine, said that this discovery may yield new treatment options that doctors can employ against chronic and persistent bacterial infections.

"Being able to disable biofilms and its protective benefits for the bacteria is a big step towards tackling the growing concern of antibiotic resistance," said Assoc Prof Pethe.

"While the scientific community is developing new types of antibiotics and antimicrobial treatments, this discovery may help to buy time by improving the effectiveness of older drugs."

NTU researchers make breakthrough to tackle growing concern of antibiotic resistance

Promising discovery in fight against antibiotic-resistant bacteria .....

Researchers at  the  University  of British  Columbia  have identified a small molecule  that prevents  bacteria from forming into biofilms, a frequent cause of infections. The anti-biofilm peptide works on a range of bacteria including many that cannot be treated by antibiotics...

Hancock and his colleagues found that the peptide known as 1018  consisting of just 12 amino acids, the building blocks of protein  destroyed biofilms and prevented them from forming.

Bacteria are generally separated into two classes, Gram-positives and Gram-negatives, and the differences in their cell wall structures make them susceptible to different antibiotics. 1018 worked on both classes of bacteria as well as several major antibiotic-resistant pathogens, including Pseudomonas aeruginosa, E. coli and MRSA.

"Antibiotics are the most successful medicine on the planet. The lack of effective antibiotics would lead to profound difficulties with major surgeries, some chemotherapy treatments, transplants, and even minor injuries," says Hancock. "Our strategy represents a significant advance in the search for new agents that specifically target bacterial biofilms."

Promising discovery in fight against antibiotic-resistant bacteria 

Drug may guard against periodontitis, related chronic diseases

A drug currently used to treat intestinal worms could protect people from periodontitis, an advanced gum disease, which untreated can erode the structures   including bone   that hold the teeth in the jaw. The research was published ahead of print in Antimicrobial Agents and Chemotherapy. Current treatment for periodontitis involves scraping dental plaque, which is a polymicrobial biofilm, off of the root of the tooth. Despite this unpleasant and costly ordeal, the biofilm frequently grows back. But the investigators showed in an animal model of periodontitis that the drug Oxantel inhibits this growth by interfering with an enzyme that bacteria require for biofilm formation, says corresponding author Eric Reynolds, of the University of Melbourne, Australia. It does so in a dose-dependent manner, indicating efficacy.

The researchers began their search for a therapy for periodontitis by studying the symbioses of the periodontal pathogens, using genomics, proteomics, and metabolomics, in animal models of periodontitis. They soon found that the periodontal biofilm depended for growth on the availability of iron and heme (an iron-containing molecule related to hemoglobin), and that restricting these reduced levels of the enzyme, fumarate reductase. Since Oxantel (see structure)  was known to inhibit fumarate reductase in some bacteria, they then successfully tested its ability to inhibit fumarate reductase activity in Porphyromonas gingivalis, one of the major bacterial components of periodontitis biofilms. Fumarate reductase is absent from humans, making it an ideal drug target.

They also showed that Oxantel disrupted the growth of polymicrobial biofilms containing P. gingivalis, Tannerella forsythia, and Treponema denticola, a typical composition of periodontal biofilms, despite the fact that the latter alone is unaffected by Oxantel.

The researchers found that treatment with Oxantel downregulated six P. gingivalis gene products, and upregulated 22 gene products, all of which are part of a regulon (a genetic unit) that controls availability of heme.

Periodontitis affects an estimated 30-47 percent of the adult population with severe forms affecting 5-10 percent. It also increases the risks of diabetes, heart disease, stroke, arthritis, and dementia, says Reynolds. These risks arise due to the pathogenic bacteria that enter the blood stream from periodontitis, as well as from the chronic inflammation caused by this disease, he says. Additionally, periodontitis correlates with increased risk of cancers of the head and neck, the esophagus, the tongue, and the pancreas, the investigators report.

http://aac.asm.org/content/early/2013/10/22/AAC.01375-13

Drug may guard against periodontitis, related chronic diseases

2-aminoimidazole/triazole conjugate re-sensitizes multi-drug resistant strains of bacteria to the effects of conventional antibiotics...

We know that infections from antibiotic-resistant bacteria such as MRSA  are especially difficult to get rid of because the bacteria can attach to surfaces and then create biofilms, sticky layers of cells that act as a shield and prevent antibiotics from destroying the bacteria underneath. While a limited number of existing antibiotics may destroy part of the biofilm, enough bacteria survive to create a recurring infection as soon as antibiotic therapy stops, and over time the surviving bacteria build resistance to that antibiotic. Though I have covered some recent developments in the MRSA field, the following findings are  really interesting for me...

Now researchers lead by Dr. Christian Melander, from North Carolina State University have found that, 2-aminoimidazole/triazole conjugate will  re-sensitize multi-drug resistant strains of bacteria to the effects of conventional antibiotics (including MRSA and multi-drug resistant Acinetobacter baumannii), apart from the synergistic effect between  the  conjugate and antibiotics toward dispersing pre-established biofilms. 

Melander and his team, in collaboration with NC State biochemist John Cavanagh, found that pre-treating the bacteria with their compound and then introducing the antibiotic penicillin one hour later increased the penicillin's effectiveness 128-fold, even when the bacteria was penicillin resistant. The antibiotics also provided a 1,000-fold enhancement to the ability of the 2-aminoimidazole to disperse biofilms. 

Researchers conclude that, compound cooperates with conventional antibiotics, overcoming an infectious threat that would otherwise persist if treated with either agent individually.....

Ref : http://aac.asm.org/cgi/content/abstract/AAC.01418-09v1

Natural product darwinolide may help combat fatal MRSA infection

A serious and sometimes fatal bacterial infection, known as methicillin-resistantStaphylococcus aureus (MRSA), may soon be beatable thanks to the efforts of University of South Florida scientists who have isolated and tested an extract from a sponge found in Antarctica. The sponge extract, known as Dendrilla membranosa, yields a new, natural product chemical which has shown in laboratory tests that it can eliminate more than 98 percent of MRSA cells. The research team has named the new chemical "darwinolide."

The study describing their methods and results was published this week in the American Chemical Society's journal Organic Letters.

While years ago the highly-resistant MRSA infection was particularly problematic in places such as hospitals and nursing homes, it has developed into an infection that can be found in commonly-used places such as gyms, locker rooms and schools.

"In recent years, MRSA has become resistant to vancomycin and threatens to take away our most valuable treatment option against staph infections," said study co-author and USF microbiologist Dr. Lindsey N. Shaw.

MRSA is unique in that it can cause infections in almost every niche of the human host, from skin infections, to pneumonia, to endocarditis, a serious infection of tissues lining the heart. Unfortunately, the pace of the pharmaceutical industry's efforts to find new antibiotics to replace those no longer effective has slowed in recent years, said Shaw.

Like many other bacterium, the MRSA bacteria forms a biofilm.

"Biofilms, formed by many pathogenic bacteria during infection, are a collection of cells coated in a variety of carbohydrates, proteins and DNA," said Shaw. "Up to 80 percent of all infections are caused by biofilms and are resistant to therapy. We desperately need new anti-biofilm agents to treat drug resistant bacterial infections like MRSA."

USF chemistry professor Dr. Bill Baker and colleagues have literally gone to the 'ends of the Earth' to help in the fight against MRSA. Baker, who also serves as director of the USF Center for Drug Discovery and Innovation (CDDI), studies the chemical ecology of Antarctica and dives in the frigid waters near Palmer Station to retrieve marine invertebrates, such as sponges, to carry out "natural product isolation," which means drawing out, modifying and testing natural substances that may have pharmaceutical potential.

His group led the effort to extract and characterize chemical structures to create darwinolide from the freeze-dried Antarctic sponges and then test in Shaw's lab to determine its effectiveness against the MRSA bacteria.

"When we screened darwinolide against MRSA we found that only 1.6 percent of the bacterium survived and grew. This suggests that darwinolide may be a good foundation for an urgently needed antibiotic effective against biofilms," said Baker, whose research team "rearranged" the chemical composition of the extracted sponge.

In the last 70 years, despite the discovery and use of antibiotics to treat infections, bacterial disease remains the second-leading cause of death globally, especially among children and the elderly, noted the researchers. In the U.S. alone there are two million hospital acquired infections annually with at least 100,000 deaths, many resulting from bacteria resistant to current antibiotics.

"We suggest that darwinolide may present a highly suitable scaffold for the development of urgently needed, novel, anti-biofilm-specific antibiotics," concluded the researchers.

Ref : http://pubs.acs.org/doi/abs/10.1021/acs.orglett.6b00979?journalCode=orlef7

Natural product darwinolide may help combat fatal MRSA infection: A serious and sometimes fatal bacterial infection, known as methicillin-resistant Staphylococcus aureus (MRSA), may soon be beatable thanks to the efforts of University of South Florida scientists who have isolated and tested an extract from a sponge found in Antarctica.

Antimicrobial peptides are promising alternative for combatting antimicrobial resistance

We know that, Antimicrobial peptides (AMPs), also called host defense peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears as though antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.

Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure. Antimicrobial peptides are generally between 12 and 50 amino acids. These peptides include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and a large proportion (generally >50%) of hydrophobic residues. The secondary structures of these molecules follow 4 themes, including i) α-helical, ii) β-strandeddue to the presence of 2 or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended. Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. It contains hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule.. This amphipathicity of the antimicrobial peptides allows them to partition into the membrane lipid bilayer. The ability to associate with membranes is a definitive feature of antimicrobial peptides^[ although membrane permeabilization is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.

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Overuse of antibiotics has led to the spread of multi-resistant bacteria that do not respond to conventional treatments. Some 700 000 people worldwide die from antimicrobial resistance each year and the future social and economic costs will be huge if nothing is done. New treatment strategies for bacterial infections are desperately needed.

Antimicrobial peptides (AMPs) are a promising alternative for treating infections because they kill bacteria by destroying their enclosing membrane, causing them to disintegrate.

AMPs are fast acting and non-specific; they attack many different bacterial strains. Infectious bacteria are less prone to developing resistance to AMPs, making them an exciting candidate for future treatment strategies.

However, few AMP-based therapies are available because they have low stability – they quickly degrade in storage and during treatment. The challenge is to get AMPs to the site of an infection in the dosage needed and without degradation.

The EU-funded FORMAMP project developed nanotechnology-based carriers to deliver AMPs directly to infected tissue. Encasing AMPs in nanoparticles helped protect them from degradation, with impressive implications.

“FORMAMP showed that structured nanoparticles are efficient delivery vehicles for a range of antimicrobial peptides needed for effective therapy,” explains project coordinator Lovisa Ringstad of RISE, Research Institutes of Sweden.

“Nanoparticles can overcome the major obstacle to peptide-based therapies that promise much in the fight against antimicrobial-resistant infections. For example, in the project we identified highly effective AMPs to combat tuberculosis. This is so promising that we are now seeking collaborators and funding for further development and to move towards eventual clinical testing.”

Fast, controlled delivery

Secondary skin infections in wounds and burns can involve several varieties of infectious bacteria – so a non-specific AMP offers obvious benefits. FORMAMP developed cream and gel formulations that are effective in delivering AMPs to the infected site and releasing them at a controlled rate.

To combat tuberculosis infections, researchers loaded porous silica nanoparticles with specially selected AMPs. Selected nanoparticles also proved very effective in penetrating the bacterial biofilm present in the lungs of cystic fibrosis patients and in wound infections that can act as a significant barrier to otherwise effective treatments.

And the benefits go beyond the ‘magic bullet’ effect of the nanoparticles, says Ringstad. “Most conventional antibiotics are delivered through pills or injections, and if they underperform then more are prescribed. We have focused on treating skin and lung infection locally, thereby reducing exposure and making treatment easier for the patient. Local delivery strategies using nanoparticles can be more cost-effective, as they use less of the active ingredient, and have fewer side effects for the same reason.”

FORMAMP was a proof-of-concept, preclinical laboratory-based project. The researchers explored several nanoparticles, such as porous silica particles, liquid crystaline nanoparticles and dendrimers – star-shaped macromolecules. Desirable properties included non-toxicity and the ability to absorb, protect and release AMPs.

The project examined skin-wound and pulmonary infections, and specialist partners provided a range of AMPs known to work with these conditions.

“One important result concerned the effect of nanoparticles on biofilms,” explains Ringstad. “Biofilms are aggregations of infectious bacteria which protect the infected area against antibiotics and other therapies – they are common in many types of infection and are difficult to penetrate. We found that when nanoparticles are loaded with AMPs then the degradation of the biofilm was significantly improved. This ability to successfully attack biofilms is a very significant result for treating conditions such as cystic fibrosis and burn wound infections.”

The research resulted in many scientific publications and several promising patents that should benefit the SME partners.

Ringstad emphasizes the importance of FORMAMP results. “The nanoparticle delivery mechanism is not limited to treating infections – it could be used in a broad range of therapies. With further research, nanotherapeutics could possibly deliver more effective treatments with fewer side effects and at a lower cost for a wide range of conditions”.

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More at : 

Honey offers new approach to fighting antibiotic resistance ............

In continuation of my update on Honey..

Honey, that delectable condiment for breads and fruits, could be one sweet solution to the serious, ever-growing problem of bacterial resistance to antibiotics, researchers said in Dallas* today. Medical professionals sometimes use honey successfully as a topical dressing, but it could play a larger role in fighting infections, the researchers predicted.

"The unique property of honey lies in its ability to fight infection on multiple levels, making it more difficult for bacteria to develop resistance," said study leader Susan M. Meschwitz, Ph.D. That is, it uses a combination of weapons, including hydrogen peroxide, acidity, osmotic effect, high sugar concentration and polyphenols -- all of which actively kill bacterial cells, she explained. The osmotic effect, which is the result of the high sugar concentration in honey, draws water from the bacterial cells, dehydrating and killing them.

In addition, several studies have shown that honey inhibits the formation of biofilms, or communities of slimy disease-causing bacteria, she said. "Honey may also disrupt quorum sensing, which weakens bacterial virulence, rendering the bacteria more susceptible to conventional antibiotics," Meschwitz said. Quorum sensing is the way bacteria communicate with one another, and may be involved in the formation of biofilms. In certain bacteria, this communication system also controls the release of toxins, which affects the bacteria's pathogenicity, or their ability to cause disease.

Meschwitz, who is with Salve Regina University in Newport, R.I., said another advantage of honey is that unlike conventional antibiotics, it doesn't target the essential growth processes of bacteria. The problem with this type of targeting, which is the basis of conventional antibiotics, is that it results in the bacteria building up resistance to the drugs.

Honey is effective because it is filled with healthful polyphenols, or antioxidants, she said. These include the phenolic acids, caffeic acid, p-coumaric acid and ellagic acid, as well as many flavonoids. "Several studies have demonstrated a correlation between the non-peroxide antimicrobial and antioxidant activities of honey and the presence of honey phenolics," she added. A large number of laboratory and limited clinical studies have confirmed the broad-spectrum antibacterial, antifungal and antiviral properties of honey, according to Meschwitz.

She said that her team also is finding that honey has antioxidant properties and is an effective antibacterial. "We have run standard antioxidant tests on honey to measure the level of antioxidant activity," she explained. "We have separated and identified the various antioxidant polyphenol compounds. In our antibacterial studies, we have been testing honey's activity against E. coli, Staphylococcus aureus and Pseudomonas aeruginosa, among others."

Honey offers new approach to fighting antibiotic resistance  

Garlic compound 100 times more effective than antibiotics at fighting food borne illness...

A recent research reveals a potent effect for garlic against the bacteria Campylobacter jejuni, a leading cause of intestinal illness caused by eating undercooked poultry or foods that have been contaminated during poultry preparation. "Campylobacter is simply the most common bacterial cause of food-borne illness in the United States and probably the world," explained coauthor Michael Konkel of Washington State University's College of Veterinary Medicine.

The researchers compared the effects of diallyl sulfide (see structure),  a compound that occurs in garlic, and the antibiotics ciprofloxacin and erythromycin on biofilms formed by Campylobacter jejuni. Biofilms are colonies of bacteria protected by a film that renders them a thousand times more resistant to antibiotics than free cells. Cell death following the administration of diallyl sulfide occurred at a concentration of resveratrol that was 100-fold less than that which was effective for either antibiotic, and often took less time to work. The team found that diallyl sulfide combined with a sulfur-containing enzyme, which altered the cells' function and metabolism.

Researchers conclude that, diallyl sulphide elicits strong antimicrobial activity against planktonic and sessile C. jejuni and may have applications for reducing the prevalence of this microbe in foods, biofilm reduction and, potentially, as an alternative chemotherapeutic agent for multidrug-resistant bacterial strains.

Ref : http://jac.oxfordjournals.org/content/early/2012/04/27/jac.dks138.abstract?sid=71685bd6-4b80-4d25-b97b-9422ba1d8cc3

Antibacterial in your toothpaste may combat severe lung disease

In continuation of my update on Triclosan

A common antibacterial substance found in toothpaste may combat life-threatening diseases such as cystic fibrosis, or CF, when combined with an already FDA-approved drug.

Michigan State University researchers have found that when triclosan, a substance that reduces or prevents bacteria from growing, is combined with an antibiotic called tobramycin, it kills the cells that protect the CF bacteria, known as Pseudomonas aeruginosa, by up to 99.9 percent.

CF is a common genetic disease with one in every 2,500 to 3,500 people diagnosed with it at an early age. It results in a thick mucus in the lungs, which becomes a magnet for bacteria.

These bacteria are notoriously difficult to kill because they are protected by a slimy barrier known as a biofilm, which allows the disease to thrive even when treated with antibiotics.

"The problem that we're really tackling is finding ways to kill these biofilms," said Chris Waters, lead author of the study and a microbiology professor.

According to Waters, there are many common biofilm-related infections that people get such as ear infections and swollen, painful gums caused by gingivitis. But more serious, potentially fatal diseases join the ranks of CF including endocarditis, or inflammation of the heart, as well as infections from artificial hip and pacemaker implants.

The research is published in the journal Antimicrobial Agents and Chemotherapy.

Waters and his co-authors, Michael Maiden and Alessandra Hunt, grew 6,000 biofilms in petri dishes, added in tobramycin along with many different compounds, to see what worked better at killing the bacteria. Twenty-five potential compounds were effective, but one stood out.

"It's well known that triclosan, when used by itself, isn't effective at killing Pseudomonas aeruginosa," Hunt said, a post-doctoral associate of microbiology and molecular genetics. "But when I saw it listed as a possible compound to use with tobramycin, I was intrigued. We found triclosan was the one that worked every time."

Triclosan has been used for more than 40 years in soaps, makeup and other commercial products because of its antibacterial properties. Recently, the FDA ruled to limit its use in soaps and hand sanitizers due to insufficient data on its increased effectiveness and concern that it was being overused. Clear evidence has shown, though, that its use in toothpaste is safe and highly effective in fighting gingivitis, and it is still approved for use.

"Limiting its use is the right thing to do," Maiden said, a graduate student in medicine. "The key is to avoid creating resistance to a substance so when it's found in numerous products, the chances of that happening increase."

Tobramycin  (below structure) is currently the most widely used treatment for CF, but it typically doesn't clear the lungs of infection, Waters said. Patients typically inhale the drug, yet find themselves chronically infected their whole lives, eventually needing a lung transplant.

"Most transplants aren't a viable option though for these patients and those who do have a transplant see a 50 percent failure rate within five years," he said. "The other issue is that tobramycin can be toxic itself."

Known side effects from the drug include kidney toxicity and hearing loss.

"Our triclosan finding gives doctors another potential option and allows them to use significantly less of the tobramycin in treatment, potentially reducing its use by 100 times," Hunt said.

Within the next year, Waters and his colleagues will begin testing the effectiveness of the combination therapy on mice with hopes of it heading to a human trial soon after since both drugs are already FDA approved.

Just brushing your teeth with toothpaste that has triclosan won't help to treat lung infections though, Maiden said.

"We're working to get this potential therapy approved so we can provide a new treatment option for CF patients, as well as treat other biofilm infections that are now untreatable. We think this can save lives."

Bromo furanones a new class of antimicrobials.....

We know that Candida albicans is the most virulent  Candida species of medical importance, which presents a great threat to immunocompromised individuals such as HIV patients. Candida albicans is carried by about 75 percent of the public. Typically the fungus is harmless but, in individuals with HIV or otherwise compromised immune systems, it can cause candidiasis, which has a high mortality rate. The fungi can also form biofilms that attach to surfaces and are up to 1,000 times more resistant to anti-fungals.

Currently, there are only four classes of antifungal agents available for treating fungal infections: azoles (Diflucan, flucanazole), polyenes, pyrimidines, and echinocandins. The fast spread of multidrug resistant C. albicans strains has increased the demand for new antifungal drugs.

Now two Syracuse University scientists have developed new brominated furanones (see structure) that exhibit powerful anti-fungal properties.

As per the claim by the researchers, the compound exhibited more than 80 percent. Structure and activity of this class of furanones reveals that the exocyclic vinyl bromide conjugated with the carbonyl group is the most important structural element for fungal inhibition. Furthermore, gene expression analysis using DNA microarrays showed that 3 μg/mL of 4-bromo-5Z-(bromomethylene)-3-butylfuran-2-one (BF1) upregulated 32 C. albicans genes with functions of stress response, NADPH dehydrogenation, and small-molecule transport, and repressed 21 genes involved mainly in cell-wall maintenance.

Interestingly, only a small overlap is observed between the gene expression changes caused by the representative brominated furanone in this study and other antifungal drugs reported in literature. This result suggests that brominated furanones and other antifungal drugs may target different fungal proteins or genes.

The existence of such new targets provides an opportunity for developing new agents to control fungal pathogens which are resistant to currently available drugs.

The research team has also shown previously that these furanones inhibit bacterial biofilm formation; thus they may help control chronic infections where biofilms often appear, on surgical, dental and other implants. Hope broad spectrum of other potential capabilities make this class of compounds a new way to combat the microbes in the days to come...

Ref : http://springerlink.com/content/92735526v5013088/

Mystery of Bacterial Growth and Resistance Resolved ?

In continuation of my update on the mechanism of bacterial resistance...

Scientists at The Scripps Research Institute have unraveled a complex chemical pathway that enables bacteria to form clusters called biofilms. Such improved understanding might eventually aid the development of new treatments targeting biofilms, which are involved in a wide variety of human infections and help bacteria resist antibiotics. 

Biofilm formation is a critical phenomenon that occurs when bacterial cells adhere to each other and to surfaces, at times as part of their growth stage and at other times to gird against attack. In such aggregations, cells on the outside of a biofilm might still be susceptible to natural or pharmaceutical antibiotics, but the interior cells are relatively protected. This can make them difficult to kill using conventional treatments.

Past research had also revealed that nitric oxide is involved in influencing bacterial biofilm formation. Nitric oxide in sufficient quantity is toxic to bacteria, so it's logical that nitric oxide would trigger bacteria to enter the safety huddle of a biofilm. But nobody knew precisely how. In the new study, the scientists set out to find what happens after the nitric oxide trigger is pulled. "The whole project was really a detective story in a way," said Plate.

To learn more, the researchers used a technique called phosphotransfer profiling. This involved activating the histidine kinase and then allowing them to react separately with about 20 potential targets. Those targets that the histidine kinase rapidly transferred phosphates to had to be part of the signaling pathway.

"It's a neat method that we used to get an answer that was in fact very surprising," said Plate. 

The experiments revealed that the histidine kinase phosphorylated three proteins called response regulators that work together to control biofilm formation for the project's primary study species, the bacterium Shewanella oneidensis, which is found in lake sediments.

Further work showed that each regulator plays a complementary role, making for an unusually complex system. One regulator activates gene expression, another controls the activity of an enzyme producing cyclic diguanosine monophosphate, an important bacterial messenger molecule that is critical in biofilm formation, and the third tunes the degree of activity of the second.

Since other bacterial species use the same chemical pathway uncovered in this study, the findings pave the way to further explore the potential for pharmaceutical application. As one example, researchers might be able to block biofilm formation with chemicals that interrupt the activity of one of the components of this nitric oxide cascade.

Ref : http://www.scripps.edu/news/press/2012/20120426marletta.html

http://www.sciencedirect.com/science/article/pii/S1097276512002602

WPI Research Shows How Cranberry Juice Fights Bacteria at the Molecular Level

The study tested proanthocyanidins or PACs, a group of flavonoids found in cranberries. Because they were thought to be the ingredient that gives the juice its infection-fighting properties, PACs have been considered a hopeful target for an effective extract. The new WPI report, however, shows that cranberry juice, itself, is far better at preventing biofilm formation, which is the precursor of infection, than PACs alone. The data is reported in the paper "Impact of Cranberry Juice and Proanthocyanidins on the Ability of Escherichia coli to Form Biofilms," which will be published on-line, ahead of print on Oct. 31, 2011, by the journal Food Science and Biotechnology.

WPI Research Shows How Cranberry Juice Fights Bacteria at the Molecular Level