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In a continuing search for compounds with antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), a chloroform extract of roots of Aralia continentalis was found to contain continentalic acid (CA, C(20)H(30)O(2)), a diterpenic acid. This compound exhibited potent activity against standard methicillin-susceptible Staphylococcus aureus (MSSA) as well as clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). It was determined that continentalic acid had minimum inhibitory concentrations (MICs) of approximately 8-16 microg/mL against S. aureus, including the MSSA and MRSA standard strains. Therefore, the results obtained in this study suggest that continentalic acid might have potential as an adjunct in the treatment of antibiotic-resistant bacteria. Copyright (c) 2006 John Wiley & Sons, Ltd.
Link: Antimicrobial Peptide
Fighting dangerous microbes has become increasingly difficult as many bacterial strains have become resistant to antibiotics. To respond to this problem, Laszlo Otvos, Jr., PhD, research professor and director of drug development at the Sbarro Institute of Cancer Research and Molecular Medicine at Temple University in Philadelphia, has developed an antimicrobial peptide - a fragment of a larger protein found in a certain insect - that can identify resistant bacteria and target them for destruction. This March, Otvos was awarded a patent for his discovery, which he hopes will lead to a new class of peptide-based antibiotic drugs. Another patent application of the inventor, identifying an unprecedented mode of action of this particular class of novel antibiotics, is currently in the prosecution stage. Along with the antimicrobial response of this peptide, Otvos' lab also identified the specific segments of the antimicrobial peptide that kill bacteria and the segments responsible for entering the cell to destroy it. "Knowing how the peptides penetrate cells may be important for future drug delivery systems, against bacteria and deranged human cells alike," says Otvos.
Link: Today Tonight on Seven.
Microbiologist professor Graeme Nimmo has just finished a study of drug-resistant super bacteria or "superbugs". He found that the bacteria were spreading further a field and they were also getting tougher. Nimmo said the superbugs were now not just resistant to one type of antibiotics, they were becoming bullet proof to a variety of drugs. Doctors said all it took to contract a superbug was an open wound and some contaminated soil. Some experts believed it was only a matter of time before superbugs could not be destroyed by any medicines at our disposal.
Link: Evolution Follows Few Of The Possible Paths To Antibiotic Resistance.
Darwinian evolution follows very few of the available mutational pathways to attain fitter proteins, researchers at Harvard University have found in a study of a gene whose mutant form increases bacterial resistance to a widely prescribed antibiotic by a factor of roughly 100,000. Their work indicates that of 120 harrowing, five-step mutational paths that theoretically could grant antibiotic resistance, only about 10 actually endow bacteria with a meaningful evolutionary advantage. The research is published in the journal Science. "Just as there are many alternate routes one might follow in driving from Boston to New York, one intrinsic property of DNA is that very many distinct mutational paths link any two variants of a gene," says lead author Daniel M. Weinreich, a research associate in Harvard's Department of Organismic and Evolutionary Biology. "Although this fact has been recognized for at least 35 years, its implications for evolution by natural selection have remained unexplored. Specifically, it is of great interest to determine whether natural selection regards these many mutational paths equivalently."
Link: Bacteria's Achilles' Heel.
Researchers at the University of California, San Diego have determined what factors turn on protein production in bacteria, a finding that provides new targets for the development of antibiotics. In the study, published in the April issue of the journal Molecular Cell, researchers Sean Studer and Simpson Joseph in UCSD's Department of Chemistry and Biochemistry report how the messenger RNA instructions to make a protein are unfolded in a bacterial cell, so that they can be read by the cell's protein-making machinery. Since unfolding the instructions is an essential step in the making of a protein, the researchers say that drugs designed to interfere with this step would make ideal antibiotics. "With antibiotic-resistant strains of bacteria on the rise, there is a crisis in the management and treatment of these infections throughout the world," said Simpson Joseph, a professor of chemistry and biochemistry who led the study. "Our results will provide insights for developing novel antibiotics that target the messenger RNA unfolding process in disease-causing bacteria."
Link: Yahoo! Finance.
Cerexa, Inc. (http://www.cerexa.com) today announced the completion of patient enrollment for its multinational Phase 2 clinical trial of ceftaroline acetate (formerly PPI-0903) in patients with complicated skin and skin structure infections (cSSSI). Ceftaroline is a next generation, broad spectrum, cephalosporin antibiotic that combines the advantage of an enhanced gram-positive spectrum, including bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA), with broad gram-negative activity. The U.S. Food and Drug Administration recently granted ceftaroline Fast Track designation for the treatment of cSSSI caused by MRSA. ADVERTISEMENT The Phase 2 trial enrolled 100 patients with cSSSI and was conducted at more than 20 study sites worldwide. The objective of this trial was to investigate the efficacy and safety of ceftaroline versus standard therapy. Cerexa initiated the Phase 2 trial in October 2005 and plans to release top- line data in the third quarter of 2006.
Link: Resistance is futile: making drugs from bugs.
Led by Professor Tony Maxwell of the John Innes Centre (Norwich, UK) [1] and Professor Lutz Heide of the Pharmazeutisches Institut, T�bingen (Germany) [2], the team has developed ways of engineering harmless soil bacteria called Streptomyces to do the difficult chemistry for them. Streptomyces naturally make antibiotics to kill other bacteria in the soil. Unfortunately these don’t make very good drugs for use in humans because they are not very soluble in water and so cannot get into the bloodstream easily. The researchers have found a way to modify the bacteria to manufacture new varieties of these antibiotics that could be developed into more effective drugs. By studying variations of two natural antibiotics produced by Streptomyces, called novobiocin and clorobiocin, the scientists are determining which parts of the molecules are essential for their antibacterial activity. They hope that by varying other parts of the molecules they can design new antibiotics with better activity and fewer side effects. Novobiocin and clorobiocin work by interfering with how DNA, the molecule that stores genetic information, is packed into the bacterial cell. The DNA in human cells is packed differently and so these cells are not affected by the antibiotics.
Link: Antimicrobial Agents and Chemotherapy.
PPI-0903 is a new cephalosporin with broad-spectrum activity, including beta-lactam-resistant Streptococcus pneumoniae and Staphylococcus aureus. We used the neutropenic murine thigh and lung infection models to examine the pharmacodynamic characteristics of PPI-0903. Serum drug levels following four fourfold-escalating single doses of PPI-0903 were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 1.56, 6.25, 25, and 100 mg/kg of body weight in mice infected with S. pneumoniae ATCC 10813, S. aureus ATCC 29213, or Escherichia coli ATCC 25922. Dose fractionation studies over a 24-h dose range of 0.39 to 1,600 mg/kg were administered every 3, 6, 12, or 24 hours.
Link: Antimicrobial Agents and Chemotherapy.
Staphylococcus aureus is among the leading pathogens causing bloodstream infections able to form biofilms on host tissue and indwelling medical devices and to persist and cause disease. Infections caused by S. aureus are becoming more difficult to treat because of increasing resistance to antibiotics. In a biofilm environment particularly, microbes exhibit enhanced resistance to antimicrobial agents. Recently, farnesol was described as a quorum-sensing molecule with possible antimicrobial properties. In this study, the effect of farnesol on methicillin-resistant and -susceptible strains of S. aureus was investigated. With viability assays, biofilm formation assessment, and ethidium bromide uptake testing, farnesol was shown to inhibit biofilm formation and compromise cell membrane integrity. The ability of farnesol to sensitize S. aureus to antimicrobials was assessed by agar disk diffusion and broth microdilution methods. For both strains of staphylococci, farnesol was only able to reverse resistance at a high concentration (150 �M). However, it was very successful at enhancing the antimicrobial efficacy of all of the antibiotics to which the strains were somewhat susceptible. Therefore, synergy testing of farnesol and gentamicin was performed with static biofilms exposed to various concentrations of both agents. Plate counts of harvested biofilm cells at 0, 4, and 24 h posttreatment indicated that the combined effect of gentamicin at 2.5 times the MIC and farnesol at 100 �M (22 �g/ml) was able to reduce bacterial populations by more than 2 log units, demonstrating synergy between the two antimicrobial agents. This observed sensitization of resistant strains to antimicrobials and the observed synergistic effect with gentamicin indicate a potential application for farnesol as an adjuvant therapeutic agent for the prevention of biofilm-related infections and promotion of drug resistance reversal.
Link: Superbug fighter sees losses rise.
NeuTec raised £25m last year to fund the final stage of development and commercialisation of the drug and ended the half-year with a cash pile of £26m. It hopes to gain market clearance to launch Mycograb at the end of this year. The company's other main product, Aurograb, targets MRSA and NeuTec has recruited 150 patients for clinical trials across Europe. Need Chairman Anthony Martin said there was a desperate need for new drugs to treat life-threatening infections. He added: "NeuTec is aggressively trying to fill this void. Bad bugs need clever drugs."
Link: New front developing in war on killer bugs
Cubist Pharmaceuticals says that its drug Cubicin, already used by doctors to treat complicated skin infections, can be effective at combating Staphylococcus aureus in the bloodstream. According to the Food and Drug Administration, S. aureus is the second-most-common bacteria identified in hospitalized patients whose blood becomes infected with bacteria. American hospitals spend $9.7 billion per year treating the resulting infections. ''The Cubist drug was tested in perhaps the toughest of all infections," said Dr. John G. Bartlett, chief of infectious disease at Johns Hopkins. ''The stakes do not get any higher, not in infectious disease." To show Cubicin's effectiveness, the company had to pull off the unprecedented feat of testing the drug against the S. aureus bacteria while it was coursing through patients' bloodstreams. The logistics of the trial were complicated: Potential trial participants had bacterial infections that could -- but not always -- lead to the heart complications the company also wanted to study. Cubist screened 5,000 patients in 76 potential study sites in six countries. Older drugs now used to treat bacteria-induced heart inflammation were studied in just a few patients. Cubist's ensuing trial cost the company an estimated $100,000 per patient for the 246 patients enrolled in the international trial, said Bartlett at Johns Hopkins, who did not participate in the trial but has studied it closely. Mike Bonney, Cubist's chief executive, said the company's ''bold decision" gives it a nearly four-year lead over its rivals. ''We persevered and got it done," Bonney said. ''I'm not convinced others will do it." Cubists' upcoming reward: the FDA's first-ever approval of a drug to treat Staphylococcus aureus bacteria in the bloodstream, which can lead to infective endocarditis, an ailment that inflames and imperils hearts.
Link: Tabebuia avellanedae
Although it has been observed toxic effect in eukaryotic cells, the compounds were shown to be atoxic when applied as topic preparations in healthy rabbits. No inhibition of proteins synthesis was observed. CONCLUSIONS: Our results suggest that quinones could be used in topic preparations against wound infections caused by staphylococci, after major investigation of the pharmacological properties of the compounds. Studies about the use of these compounds on tumoral cells could be carried on, due to their effect in eukaryotic cells metabolism.
Link: Infection and Immunity.
We investigated the potential of the S. aureus surface protein iron surface determinant B (IsdB) as a prophylactic vaccine against S. aureus infection. IsdB is an iron-sequestering protein that is conserved in diverse S. aureus clinical isolates, both methicillin resistant and methicillin sensitive, and it is expressed on the surface of all isolates tested. The vaccine was highly immunogenic in mice when it was formulated with amorphous aluminum hydroxyphosphate sulfate adjuvant, and the resulting antibody responses were associated with reproducible and significant protection in animal models of infection. The specificity of the protective immune responses in mice was demonstrated by using an S. aureus strain deficient for IsdB and HarA, a protein with a high level of identity to IsdB. We also demonstrated that IsdB is highly immunogenic in rhesus macaques, inducing a more-than-fivefold increase in antibody titers after a single immunization. Based on the data presented here, IsdB has excellent prospects for use as a vaccine against S. aureus disease in humans.
Link: Infectious Disease News.
Officials with the Infectious Diseases Society of America (IDSA) are calling on government officials to introduce and enact legislation that would offer market exclusivity to pharmaceutical companies that research and develop novel antimicrobials for “superbugs,” or highly dangerous, drug-resistant microbes. They also identified a representative “hit list” of microbes that are most in need of research — methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Klebsiella species, Acinetobacter baumannii, Aspergillus species, vancomycin-resistant Enterococcus faecium and Pseudomonas aeruginosa. In a press conference announcing the list, Martin J. Blaser, MD, president of the IDSA, and colleagues detailed complications associated with these microbes and the challenges involved in treating them. MRSA infections constitute the single most important cause of health care–associated infections, increasing lengths of hospital stay, severity of illness, deaths and costs. Although these infections occurred primarily in hospitals, they are becoming increasingly common in communities nationwide, especially where groups of people are in close quarters, including military facilities, sports teams and prisons. The number of infected children jumped 28% between 2001 and 2004, according to Blaser. Although there are treatment options available for MRSA, most medications need to be administered by injection; oral drugs are desperately needed.
Link: Inhibition
Lactobacillus reuteri RC-14 has previously been shown to inhibit Staphylococcus aureus infection in a rat surgical-implant model. To investigate the basis for this, communication events between the two bacterial species were examined. L. reuteri RC-14 and Staph. aureus Newman were grown in a co-culture apparatus that physically separates the two species, while allowing the passage of soluble compounds. Using two-dimensional gel electrophoresis (2D-E), protein expression changes in Staph. aureus were analysed in response to co-culture with medium alone, L. reuteri RC-14, and a Lactobacillus strain that did not inhibit Staph. aureus infection in the rat model. It was observed that one protein in particular, identified as staphylococcal superantigen-like protein 11 (SSL11), showed a dramatic decrease in expression in response to growth with L. reuteri RC-14. Genetic reporters that placed both gfp and lux under the transcriptional control of the SSL11 promoter confirmed the 2D-E results. Interestingly, using similar reporter gene experiments, it was observed that the Staph. aureus P3 promoter from the staphylococcal accessory gene regulator (agr) locus also showed a decrease in expression in response to growth in the presence of L. reuteri RC-14. It was further demonstrated that L. reuteri RC-14 supernatant contained small unidentified molecules that were able to repress the SSL11 and P3 promoters, but the repression of SSL11 occurred independently of the agr system. These results suggest that L. reuteri RC-14 has the potential to alter the virulence of Staph. aureus via secretion of cell–cell signalling molecules.
Link: VOA News
Martin Blaser is President of the Infectious Diseases Society of America, whose members include physicians and scientists. He says bacteria are becoming resistant faster than we can develop drugs to fight them. "The time to prepare is now because it takes years to develop new antibiotics." But Blaser says the antibiotic drug pipeline is drying up. Market forces are partially to blame. Drug companies make a lot of money with medicines for long-term chronic diseases. They see little profit in drugs to fight the increasingly resistant germs doctors see in hospitals everyday. Blaser says there are other financial roadblocks as well. "The development of resistant strains of bacteria limits the long-term market potential for an antibiotic," he says. "Also infectious disease experts may suggest restrictions on the use of new antibiotics in order to preserve the effectiveness of these drugs for those patients that need them most. Although sensible, such restrictions reduce the incentives for companies to develop new drugs." The Infectious Diseases Society of America is calling on Congress to act. IDSA policy director Robert Guidos says incentives for the pharmaceutical industry can help pave the way. "We're calling for tax credits for research, for facilities that are used to manufacture and do [research and development] for these products. And, we are also calling for the establishment of an independent commission that will identify which of these infections are the most serious and therefore for which of these incentives should apply.
Link: Pharmaceutical Business Review
Swiss biotech firm Basilea Pharmaceutica has received positive results for its first comparative phase III trial with ceftobiprole as a treatment for MRSA. Ceftobiprole showed a high cure rate and was safe and well tolerated. This first-in-class anti-MRSA broad-spectrum cephalosporin is being developed in partnership with Cilag AG International, a Johnson & Johnson company.
Link: The Hospital
-- In the highly mature and competitive antibacterial market, hospital-acquired drug-resistant infections represent the few remaining areas of high unmet medical need and expanding commercial opportunity. The significant morbidity, mortality, and cost associated with drug-resistant infections provide an important clinical incentive for development and allow companies to justify relatively premium pricing in this market. Furthermore, expected growth in the patient population, driven by demographic changes and an expanding population of critically ill patients, will fuel future growth.
-- Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species represent several of the most important drug-resistant pathogens that have been the focus of antibacterial R&D activity in recent years. With the availability of several products active against MRSA and VRE (e.g., linezolid (Pfizer's Zyvox), daptomycin (Cubist's Cubicin)), the most significant emerging threat has shifted to the gram-negative pathogens (Enterobacteriaceae, P. aeruginosa, and Acinetobacter sp.), which in many cases are resistant to most first-line antibacterials.
More at the link above
Link: Yahoo! Finance.
Cerexa, Inc. (http://www.cerexa.com) today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for PPI-0903, a next-generation, broad-spectrum, cephalosporin antibiotic, for the treatment of complicated skin and skin structure infections (cSSSI) caused by methicillin-resistant Staphylococcus aureus (MRSA). Cerexa initiated a Phase 2 trial of PPI-0903 for the treatment of cSSSI in October 2005. Under the FDA Modernization Act of 1997, the Fast Track program of the FDA is designed to facilitate the development and expedite the review of a new drug that is intended for the treatment of a serious or a life-threatening condition, and demonstrates the potential to address unmet medical needs for such a condition.
Link: The other drug war
Well researched item - more at the link above
Cubist Pharmaceuticals hasn't given up on the soil. It's seeking microbes that are so rare that they have been overlooked. To find them, the company has constructed bacteria that are resistant to most known soil antibiotics, so that only novel compounds can kill them in tests. Tally says the approach has yielded promising bacteria — and 70% of these have never been described before. But 99% of soil dwelling bacteria can't be grown in a lab, says Julian Davies, a microbiologist at the University of British Columbia in Vancouver. Many antibiotics might exist there, unknown by science, because the bugs that produce them are too finicky to be cultured. Davies and others have tried to circumvent the culturing problem not by growing the bugs, but by isolating their genes instead. They then test the ability of these genes to produce antibiotics. But so far, Davies says, success has been limited, in part because it's difficult to harvest large enough pieces of DNA from soil. Davies is studying bacteria that grow on lichens — and there he's had more luck. He's isolated about 2,000 bacterial strains that grow on lichens, and probably half have antibiotic activity, he says. Seaweeds are the source of choice for Brian Austin, a microbiologist of Scotland's Heriot-Watt University in Edinburgh. He's coaxed bacteria that grow on them to produce antibiotics, but only after using a trick: He cultured them on a household sponge from his local supermarket.
Link: Merck and Paratek
Merck & Co., Inc. and Paratek Pharmaceuticals, Inc. announced today that Paratek has entered into an exclusive, worldwide collaborative development and license agreement with Merck --through an affiliate -- for PTK 0796, a novel, broad-spectrum aminomethylcycline (AMC) antibiotic with oral and intravenous (IV) formulations currently in Phase I clinical testing. PTK 0796 represents a significant advance over the well-known tetracycline family, and has been shown to be highly effective in animal models at treating increasingly problematic, clinically prevalent infections caused by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), and by gram-negative, atypical and anaerobic bacteria, including those resistant to currently available classes of antibiotics and known to cause diseases such as pneumonias, urinary tract infections, skin diseases and blood-borne infections in both the hospital and community settings. "Merck has long been a world leader in the fight against infections, and this agreement is a further demonstration of our commitment to this field of medicine," said Peter S. Kim, Ph.D., President, Merck Research Laboratories. "We are excited about our collaboration with Paratek to develop new antibiotics that have the potential to improve the care of patients and provide physicians with new treatment options at a time of increased antibiotic resistance."
Link: The Scotsman
A SUBSTANCE which occurs naturally in milk could become a new antibiotic capable of killing off MRSA superbugs, according to new research. Nisin, discovered in 1927, has been known to be particularly good at killing bacteria, because it can do so in several different ways. However, while it is used to preserve food, it is too delicate to survive long enough in the body to be used as a drug. Scientists in the Netherlands and US have managed for the first time to create the antibiotic in a test-tube in the same way as it is made naturally, a development which should enable the creation of a "super nisin" that is tough enough to survive in the bloodstream and still kill off bacteria.
Link: Times Online.
Jon Cove, senior lecturer in the Institute for Cellular and Molecular Biology at Leeds University, is one. Two years ago, with his wife Anne Eady, principal research fellow at Leeds, he set up Syntopix, a spin-out company developing treatments for acne and MRSA skin infections. “We realised that the nature of our research wouldn’t attract funding from the usual sources for academic research, so we approached the technology transfer team at Leeds to suggest that we start a small company and attract funding from elsewhere,” Cove says. The couple received backing from the university and the Wellcome Trust, as well as from private investors. The money invested by these sources was matched by Viking, a government-backed fund to promote university spin-outs.
Link: News
Wyeth Pharmaceuticals, a division of Wyeth, announced today that it has received a "positive opinion" recommending approval for the introduction of its first-in- class antibiotic Tygacil� (tigecycline) to the European market by the Committee for Medicinal Products for Human Use (CHMP). The introduction of Tygacil to the European market will come at a time when the need for new antibiotic options to combat serious infections is increasing. "Life-threatening infections are a growing concern globally," says Dr. Joseph Camardo, Senior Vice President, Global Medical Affairs, Wyeth Pharmaceuticals. "Bacterial infections are becoming more difficult to treat. Tygacil will provide physicians with an important option for patients." The "positive opinion" is the final step before formal approval to market Tygacil in the 25 member states of the European Union, Iceland, Liechtenstein, and Norway. The CHMP recommendation of Tygacil will now be forwarded to the European Commission (EC) for final approval, which is anticipated in the second quarter of 2006.
Link: Forbes.com.
Cubist Pharmaceuticals, Inc. (Nasdaq: CBST) today announced that NASDAQ has halted trading of Cubist common stock. The Anti-Infective Drug Advisory Committee to the U.S. Food and Drug Administration (FDA) meets today to review and discuss the Supplemental New Drug Application (sNDA) for CUBICIN(R) (daptomycin for injection) seeking approval as treatment for Staphylococcus aureus (S. aureus) bacteremia including those with known or suspected endocarditis. About CUBICIN(R) (daptomycin for injection)
Link: South Florida Sun-Sentinel.
Doctors warned Wednesday of an impending crisis unless new drugs are created to fight emerging strains of bacteria that are causing more and more people to get sick with hard-to-treat infections. The infection experts said pharmaceutical companies have nearly abandoned antibiotic development because the drugs are not big moneymakers. Congress, they said, needs to pass legislation that gives manufacturers tax credits, patent extensions and other lucrative enticements for novel antibiotics. The Infectious Diseases Society of America also issued a "hit list" of the top six bacteria already endangering patients. Members of the group said resistant infections have become commonplace. "It has been going on for a long time, but it is accelerating now, and it is accelerating at a time when the pipeline for new antibiotics is running dry," said Dr. Martin J. Blaser, the society's president and a microbiology professor at New York University. The group issued the same warnings in 2004 in a lengthy report that offered details on what the government should do to spur new antibiotic development. But Congress failed to take action, the doctors said.
Link: The Annals of Pharmacotherapy.
DATA SYNTHESIS: Dalbavancin, a novel lipoglycopeptide, has a mechanism of action similar to that of other glycopeptides. It has in vitro activity against a variety of gram-positive organisms, but no activity against gram-negative or vancomycin-resistant enterococci that possess VanA gene. Due to its prolonged half-life (6-10 days), dalbavancin can be administered intravenously once weekly. In Phase II and III clinical trials, dalbavancin was effective and well tolerated for the treatment of skin and soft-tissue infections, catheter-related bloodstream infections, and skin and skin-structure infections. To date, adverse events are mild and limited; the most common include pyrexia, headache, nausea, oral candidiasis, diarrhea, and constipation. CONCLUSIONS: Dalbavancin appears to be a promising antimicrobial agent for the treatment of gram-positive infections. A new drug application was filed with the Food and Drug Administration (FDA) in December 2004. The FDA issued an approvable letter in 2005 for dalbavancin. If approved, dalbavancin is expected to be launched in the first quarter of 2006.
Link: Yahoo! Finance
Antibacterial resistance has always been an important driver of innovation for new antibacterial agents. Over the past 10-15 years, resistance to antibacterials in the hospital setting has risen dramatically. Although they are niche segments with relatively small patient populations, hospital-acquired drug-resistant infections represent the few remaining areas of high unmet medical need within the antibacterial market. With many Big Pharma companies recently choosing to withdraw from active competition in this market, these niche sectors may represent substantial new opportunities for smaller pharmaceutical companies. In this report, an overview is provided of the mechanisms of resistance and the key pathogens involved in these resistant infections, the impact of antibacterial resistance on outcomes and cost is discussed, advantages and challenges of development in this market are highlighted, the ideal characteristics of a novel hospital-based antibacterial are outlined, and the near-term pipeline is reviewed.
See link above for more
Link: HighWire Press -- Medline Abstract.
Four quinic acid gallates were isolated from the dried pods of Tara [Caesalpinia spinosa (Molina) Kuntze]. These compounds intensified the susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) to oxacillin. 3,4,5-Tri-O-galloylquinic acid methyl ester (2) was the most effective compound of them.
Link: icBirmingham
WORK on a revolutionary new vaccine to protect against hospital superbugs MRSA and clostridium difficile will be highlighted in Birmingham tomorrow. Infection expert Dr Afshan Ahmad will explain the potential of a new injection at Northfield-based MRSA Support's public meeting. He is currently working on the second stage trials for a vaccine to halt MRSA in its tracks. Tony Field, chairman of MRSA Support, said: "It is wonderful to get such a knowledgable speaker as Dr Ahmad to talk about his work. "He is developing a vaccine to protect against MRSA and if successful, it could be a real breakthrough for hospitals and the terrible number of patients affected by infections like MRSA." Dr Ahmad will be joined by medical herbalist Noreen Lopez, who explains how traditional treatments can be effective in warding off infections.
Link: The FASEB Journal.
Antimicrobial peptides (AMPs) have been shown in animal and human systems to be effective natural antibiotics. However, it is unclear how they convey protection; they often appear inactive when assayed under culture conditions applied to synthetic antibiotics. This inactivation has been associated with loss of function in physiological concentrations of NaCl or serum. In this study we show that the balance of host ionic conditions dictate microbial sensitivity to AMPs. Carbonate is identified as the critical ionic factor present in mammalian tissues that imparts the ability of AMPs such as cathelicidins and defensins to kill at physiological NaCl concentrations. After adapting to carbonate-containing solutions, global changes occur in Staphylococcus aureus and Escherichia coli structure and gene expression despite no change in growth rate. Our findings show that changes in cell wall thickness and Sigma factor B expression correspond to the increased susceptibility to the AMP LL-37. These observations provide new insight into the factors involved in enabling function of innate immune effector molecules, and suggest that discovery of new antimicrobials should specifically target pathogens as they exist in the host and not the distinctly different phenotype of bacteria grown in culture broth
Link: Yahoo! Finance.
Rib-X Pharmaceuticals, Inc., a privately held biopharmaceutical company that is designing and developing next generation antibiotics, today announced that it had initiated Phase I trials of its first candidate for treating resistant infections. The candidate had been derived from the company's Rx-01 program, which utilizes X-ray crystallography and computational chemistry to facilitate drug design. The company also announced the recent presentation of several scientific studies at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), in Washington, D.C.
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"The start of our clinical trial and our ICAAC presentations document the substantial competitive advantage of our structure-based drug design approach," said Susan Froshauer, Ph.D., President and Chief Executive Officer of Rib-X. "One key asset for the Company is our high resolution X-ray crystallographic knowledge of the 50S subunit of the ribsome in Gram-positive bacteria, the clinically validated target for many commercially important antibiotics.
Link: HighWire Press -- Medline Abstract.
The objective of this study was to investigate the in vitro activities of lauric acid and myristylamine in combination with six antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA). The combination effect of lipids and antimicrobial agents was evaluated by the checkerboard method to obtain a fractional inhibitory concentration (FIC) index. The effects of lauric acid gentamicin (GM) and lauric acid imipenem (IPM) combinations were synergistic against the clinical isolates in 12 combinations. An antagonistic FIC index was observed only with the myristylamine GM combination. We investigated in detail the antimicrobial activity for two combinations that showed a synergistic effect. The cytotoxicity of lauric acid was not enhanced by the addition of GM and IPM. In time-kill studies, lauric acid GM and lauric acid IPM combinations at one-eighth of the minimum inhibitory concentration produced a bacteriostatic effect.
Link: Journal of Biological Chemistry.
Similar to ovine cathelicidin SMAP-29, putatively mature fowlicidins displayed potent and salt-independent activities against a range of Gram-negative and Gram-positive bacteria, including antibiotic-resistant strains, with minimum inhibitory concentrations in the range of 0.4-2.0 microM for most strains. Fowlicidin-1 and -2 also showed cytotoxicity, with 50% killing of mammalian erythrocytes or epithelial cells in the range of 6-40 microM. In addition, two fowlicidins demonstrated a strong positive cooperativity in binding lipopolysaccharide (LPS), resulting in nearly complete blockage of LPS-mediated proinflammatory gene expression in RAW264.7 cells. Taken together, fowlicidin-1 and -2 are clearly among the most potent cathelicidins that have been reported. Their broad-spectrum and salt-insensitive antibacterial activities, coupled with their potent LPS-neutralizing activity, make fowlicidins excellent candidates for novel antimicrobial and anti-sepsis agents.
Link: Datamonitor
The FDA has granted Cubist's Cubicin priority review status in acute bacteremia and endocarditis. Cubist Pharmaceuticals' Cubicin has been granted priority review status by the FDA for an additional indication in patients with bacteremia with known or suspected endocarditis caused by Staphylococcus aureus. An approval in this new indication would significantly strengthen Cubicin's position in the MRSA niche market, which is expected to become increasingly competitive in the next few years. Cubicin (daptomycin), Cubist's only approved product so far, was initially launched in the US market in November 2003. The drug, a cyclic lipopetide belonging to a new class of antibacterials, is approved for the treatment of skin and skin-structure infections caused by several Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA). MRSA has historically been treated with the injectable glycopeptide vancomycin, long considered to be the treatment of choice due to strong long-term usage data, and thus physician familiarity, together with its low cost. However, the emergence of vancomycin-resistant MRSA strains and the failure of the drug to effectively penetrate certain parts of the body have driven the need for the development of new, more potent antibacterials.
Link: Datamonitor
The FDA has granted priority review status to Cubist Pharmaceuticals' supplemental new drug application for the use of the company's antibiotic Cubicin in the treatment of a condition caused by staphylococcus aureus. The FDA grants priority review to products it believes represent a therapeutic advance over existing medicines. By granting priority review status to Cubicin, the FDA has established a target date to act on the filing by March 24, 2006. Cubist submitted the application on September 26, 2005, requesting approval for a new indication at 6mg/kg for treatment of patients with bacteremia with known or suspected endocarditis caused by Staphylococcus aureus. Cubicin was originally approved on September 12, 2003, at 4mg/kg intravenously once-daily for the treatment of complicated skin and skin structure infections caused by Gram-positive organisms, including both susceptible and resistant strains of S. aureus (MSSA and MRSA respectively).
Link: Anti-MRSA ‘Super-drug' Secures Funding to Phase II Clinical Trials.
The world's first light-activated drug designed to combat hospital superbugs, including MRSA, has just secured funding through to early clinical development. Destiny Pharma Ltd, the company behind the XF drug has secured �3 million of additional investment to take development through to Phase II Clinical Development. Destiny Pharma's patented XF drugs are designed to selectively attack and eliminate bacteria; laboratory tests have confirmed they are highly potent and effective against all tested strains of Staphylococcus aureus, including MRSA and resistant strains15 and 16. Independent laboratories have confirmed that the compounds are highly potent bacterocidals with an MIC of 0.06 _g/ml against MRSA. The efficacy and safety of the XF drugs has been demonstrated in studies in-vivo, which show that XF is able to eradicate 99.99% of MRSA at concentrations where no safety issues are observed. Unlike antibiotics the XF drugs bind to every part of the bacteria, rather than to a specific receptor, lowering the potential to mutate into a resistant strain. Studies in-vitro confirm that unlike the case with traditional antibiotics, the bacteria have an extremely low propensity to evolve resistance, opening the prospect of using the XF drugs prophylactically to prevent life-threatening hospital infections.
Link: Template.cfm (application/pdf Object).
Infection doctors call on the USA govt to help aid via legislation the develpoment of new antibiotics. An important letter
Design, synthesis, and biological evaluation of several domains of the thiopeptide antibiotic thiostrepton led to the discovery of a biologically active fragment. The biological properties of this novel small organic molecule include antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF) bacterial strains, as well as cytotoxic action against a number of cancer cell lines.
Researchers from Colorado have identified a new topical antibiotic that may inhibit skin infections in humans. Their findings appear in the October 2005 issue of the journal Antimicrobial Agents and Chemotherapy. Ongoing emergence of drug-resistant bacteria continues to propel the search for new antibiotics. In the year 2000, methicillin-resistant Staphylococcus aureus (MRSA) measured an infection rate of 43.7% in U.S. hospitals, with nasal carriage as an important risk factor in transmission. Until recently, mupirocin effectively treated S. aureus and Streptococcus pyogenes skin infections, however S. aureus is now showing signs of resistance. In the study the antibacterial activity of a novel methionyl-tRNA inhibitor, REP8839, was tested against samples of S. aureus and S. pyogenes. Researchers found all isolates of S. aureus, including strains resistant to methicillin, mupirocin, vancomycin, and linezolid, to be susceptible to REP8339 as well as all isolates of S. pyogenes.
Link: Cerexa starts antibiotic trial
The private Alameda firm is studying PPI-0903 as a potential treatment for serious bacterial infections. CEO Dennis Podlesak said in a statement that early results have shown the antibiotic is well tolerated, has "excellent broad-spectrum coverage," and acts against increasingly resistant gram-positive pathogens such as methicillin-resistant staphylococcus or MRSA. The Phase II study in complicated skin infections will investigate the efficacy and safety of PPI-0903 compared with standard therapy in about 100 patients recruited from more than 20 investigational centers worldwide.
Link: A New class of antibiotics
A New class of antibiotics discovered in a forest fungus could provide a powerful weapon against superbugs, scientists said yesterday. The protein molecule, called plectasin, packs as big a punch as penicillin and vancomycin, the "last resort" antibiotic used on drug-resistant bacteria. In tests it was especially effective against bacteria responsible for meningitis, pneumonia, life-threatening sepsis, and "flesh-eating" infections, including resistant strains. Larger doses of the antibiotic were needed to have an impact on staphylococcus bacteria, including the notorious MRSA hospital superbug.
Link: Yahoo! Finance.
"We doctors have waited a long time for a new approach to antibiotic development," said Rib-X Chief Clinical Officer, Scott Hopkins, M.D. "Our ribosome technology has already enabled Rib-X to build a pipeline of compounds of distinct structural classes for both hospital- and community-based infections. This new crystal structure puts us in a unique position to target multi-drug-resistant Gram-positive bacteria like MRSA, VRE and PRSP that cause life-threatening infections. The use of the new structure will enhance our accuracy in designing new antibiotics, putting us in an even stronger position to rapidly produce drugs with increased efficacy against infections caused by drug-resistant bacteria."
Link: SinoFresh Makes Progress
SinoFresh HealthCare is offering a North American License for a Phase III drug for the treatment of a variety of upper respiratory conditions. The Drug referred to as Rhinox(TM), is the lead drug indication for the treatment of both Chronic Rhinitis and Chronic Sinusitis (CRS). Follow-on indications to rapidly follow will be for a variety of indications to include: * Methicillin Resistant Staphylococcus Aureus (MRSA) * Viral and Cold Prevention Michael Geranen, Managing Director at CAM-Global, stated, "Given the short timeline to begin phase III clinical trials and the large market size the lead drug Rhinox(TM) will be competing in, this project is highly attractive to a Pharmaceutical company seeking to gain a late stage drug development program. Compensation to SinoFresh will likely be in line with industry norms and provide compensation equivalent to a Phase III program. Such compensation would be in the form of an upfront technology transfer fee upon signing the Licensing Agreement with follow-on milestone payments and future royalties resulting in an on-going revenue stream for SinoFresh. We are considering Licensing rights outside of North America for Viral and Cold prevention, as well as MRSA and CRS."
Link: Scientific American.com
MRSA carry a unique protein called PBP 2a on the cell membrane that plays a key role in helping to defend against antibiotics. In February, Shahriar Mobashery of Notre Dame University and his colleagues identified specific components of the bacterial cell wall that interact with PBP 2a to form a chemical barricade. The team has now made three new synthetic antibiotics based on cephalosporin, a close relative of penicillin. The compounds contain protein components that mimic the crucial parts of the cell wall that cooperate with PBP 2a, which leads to its deactivation and forces the bacterium to succumb to the medication. "We are the first to demonstrate this unique strategy," Mobashery says, "which could provide a new line of defense against the growing problem of antibiotic resistance." ADVERTISEMENT (article continues below) The scientists tested the novel compounds against vancomycin-resistant MRSA and found that they successfully killed the bacteria, whereas a class of conventional antibiotics known as beta-lactams did not. One of the compounds has since begun Phase I clinical studies, but it will take more studies and time before it can be widely marketed. "As scientists, we're trying to stay one step ahead of the bacteria," Mobashery notes. "The more strategies there are to fight resistance, the better." --Sarah Graham
Link: Surrey Advertiser - Business.
A RESEARCH-based biopharmaceutical company at the University of Surrey’s research Park has made a significant breakthrough in the discovery of an antibiotic to fight the deadly MRSA virus. RecombinoGen Ltd, which was set up last November to develop new antibiotics, has discovered a drug which is able to kill superbugs such as MRSA (methicillin resistant staphylococcus aureus) in a petri dish. But to see if it works on humans and to turn it into a commercially viable proposition, the company will need to raise around �5 million. The company has already joined the university’s SETsquared centre on the Surrey Research Park to prepare for investment funding, crucial to its future. And following a series of meetings this week, it is hopeful to acquire a grant from either a major charity and a venture capitalist or by forming an alliance with another company.
Link: Guardian Unlimited
A British professor believes he has found a new antibiotic that could combat the MRSA superbug and is trying to raise £5m to fund its development. The battle against bacteria once looked as if it had been won, but the recent emergence of new bugs that cannot be treated with conventional antibiotics has rekindled interest in the area. Professor Colin Smith, of the University of Surrey, has found potential new drugs that kill such "superbugs" in a petri dish, and wants to raise cash from venture capitalists to see if they will work in humans. He has founded a company, RecombinoGen, chaired by Robert Mansfield, who used to run UK biotech Vernalis. Newcastle University's Dr Jem Stach also thinks he has found a potential new bug killer and is looking at commercialising it.
Link: ViroPharma
ViroPharma Incorporated is committed to the development and commercialization of products that address serious diseases treated by physician specialists and in hospital settings. ViroPharma commercializes Vancocin(r) approved for oral administration for treatment of antibiotic-associated pseudomembranous colitis caused by Clostridium difficile and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains
Link: Times Online.
Pfizer today announced the $1.9 billion (£1.02 billion) purchase of Vicuron, a biopharmaceutical company that has developed a drug to combat MRSA, the hospital-acquired infection that is resistant to the most common antibiotics. * The $1.9 billion price tag represents an 84 per cent premium on Vicuron’s closing share price yesterday, and gave a much-needed boost to the biotechnology sector.
Link: Infection and Immunity.
These findings show that an increased antimicrobial activity phenotype is provided by the elafin molecule and have implications for its use in S. aureus-associated local and systemic infections.
Link: EDP24 - UEA scientists aim for MRSA breakthrough.
Researchers from the University of East Anglia are co-ordinating scientific investigations that may lead to a breakthrough in the fight against hospital superbugs such as MRSA. They believe seabed work they are conducting could have a significant impact on efforts to help control antibiotic-resistant infections. The UEA's School of Environmental Sciences is co-ordinating a five-year project studying microscopic organisms in the ocean. DNA-analysis techniques have enabled the research teams to discover major new groups of organisms including small floating plants, the viruses that infect them and the bacteria that live in marine muds and sediments. But what has most excited researchers is a discovery that the marine species of actinomycetes produce a chemical called Abyssomicin C – which is effective in killing MRSA. However, they also warn it could be years before they are close to discovering how effective this breakthrough could be in fighting a superbug that is the scourge of hospital wards across the UK.
Link: BBC NEWS.
A bacterium found 300 metres below sea could be used to fight the superbug MRSA, scientists believe. UK experts from the Universities of Kent and Newcastle found a new species of a common bacterium that lives in the sea beds of Japan can kill MRSA. Actinomycete bacteria are known for their antibiotic properties. The new species, verrucosispora maris, produces a unique antibiotic, abyssomicin C.
Link: Scotsman.com News
A CURE for the deadliest strains of MRSA superbug is being developed by a Scots scientist from a plant used in soap and shampoo. Dr Valerie Ferro, an immunologist at Strathclyde University, is working to identify a chemical compound in the aloe vera plant which kills bacteria that have become resistant to all existing antibiotics. MRSA has caused the deaths of thousands of people a year and closed hospital wards where poor hygiene has allowed it to spread. Comedian Rikki Fulton, who died from MRSA, and singer Edwyn Collins, have been recent high- profile victims. Recent studies have shown bacteria are becoming increasingly resistant to antibiotics and an "arms race" has broken out as scientists try to stay one step ahead.
Link: Activity of medicinal plant
Abstract Aqueous and ethanolic extracts of ten traditional Thai medicinal plants were investigated for their ability to inhibit 35 hospital isolates of methicillin-resistant Staphylococcus aureus (MRSA). Nine medicinal plants displayed activity against all isolates tested. Ethanolic extracts of Garcinia mangostana, Punica granatum and Quercus infectoria were most effective, with MICs for MRSA isolates of 0.05-0.4, 0.2-0.4 and 0.2-0.4 mg/mL, respectively, and for S. aureus ATCC 25923 of 0.1, 0.2 and 0.1 mg/mL, respectively. MBCs for MRSA isolates were 0.1-0.4, 1.6-3.2 and 0.4-1.6 mg/mL, and for S. aureus ATCC 25923 were 0.4, 3.2 and 1.6 mg/mL, respectively.
Link: Pig molecule to combat superbugs.
Far be it from me to be a doubter but animals and human biology rarely mix in a positive way
Pigs produce the key compound Scientists believe pigs could provide a new weapon to help fight off hospital infections, and maybe superbugs such as MRSA. They have found an anti-bacterial agent produced by the animals can help prevent skin infection in humans. The molecule - PR39 - is from a family of protective proteins called cathelicidins. The University of California at San Diego study is published in Proceedings of the National Academy of Sciences. Tests showed that PR39 in combination with a human cathelicidin can kill streptococcal bacteria. When scientists delivered PR39 to human skin cells in the laboratory, the cells were better able to fend off infection by the bugs.
Link: InPharm.com - life support for the pharmaceutical industry.
The FDA's decision to grant Wyeth's tigecycline priority review status is a welcome one. Wyeth recently presented data on tigecycline, the first drug in a novel class of antibiotics, which showed that the drug demonstrated efficacy against a wide variety of bacterial infections, including MRSA. Tigecycline's entry onto the market would be timely, as global concern mounts over such 'superbugs'. Despite fears that the world may be running out of effective antibiotics, data presented at the recent European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) on various compounds highlighted that potential advances in the battle against drug resistance bacterial infections are not too far away. One such drug offering hope against resistant infections is Wyeth's candidate tigecycline, provisionally known as Tygacil, which was submitted for approval in December 2004. Tigecycline is the first in a new class of antibacterials known as glycylcyclines, and is derived from the minocycline molecule. It has demonstrated activity against tetracycline-resistant gram-positive and gram-negative pathogens, with an identical mode of action to tetracycline except for the position nine substitution of tigecycline, which provides additional steric hindrance features and resulting greater spectrum of activity.
Link: Methicillin-Resistant Staphylococcus Aureus
"There is a clear need in the market for therapeutic alternatives to currently marketed agents for treating MRSA," said Aarti Raja, Ph.D., analyst at Decision Resources. "Vancomycin (Eli Lilly's Vancocin, generics) and linezolid (Pfizer's Zyvox/Zyvoxid) are the current drugs of choice, but these products have important limitations. Zyvox/Zyvoxid is expensive and has side effects, including myelosuppression, while vancomycin offers suboptimal activity against staphylococci and a problematic side effect profile." New therapeutic approaches to MRSA infections include monoclonal antibodies, which may be useful in treating immunocompromised individuals suffering life-threatening infection. Because they will be used in combination with antibiotics, they will have an additive effect on the MRSA drug market.
Link: Synthetic route could revitalise tetracycline research.
In an editorial accompanying the study, Chaitan Khosla of Stanford University and Yi Tang of the University of California Los Angeles – who have themselves developed new biosynthetic strategies for making polyketides (the overarching chemical group which counts tetracycline as a member) – said the technique ‘enormously expands the armamentarium of the tetracycline medicinal chemist’. Tetracycline research has not been completely barren however. One tetracycline-related product from Wyeth, called tigecycline, has reached late-stage development and is tipped to become a major player the fight against multidrug-resistant micro-organisms, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci and resistant Gram-negative infections.
Link: Antibacterial activity of alpha-mangostin - Hubmed
Alpha-Mangostin, isolated from the stem bark of Garcinia mangostana L., was found to be active against vancomycin resistant Enterococci (VRE) and methicillin resistant Staphylococcus aureus (MRSA), with MIC values of 6.25 and 6.25 to 12.5 microg/ml, respectively. Our studies showed synergism between alpha-mangostin and gentamicin (GM) against VRE, and alpha-mangostin and vancomycin hydrochloride (VCM) against MRSA. Further studies showed partial synergism between alpha-mangostin and commercially availab