Scientists Studying Bacteria And Antibiotics At The Atomic Level See Potential To Create Antibiotics Less Vulnerable To Resistance

A new understanding of an enzyme important for the transfer of genetic information in bacteria may help scientists improve current antibiotics and also create antibiotics that are less vulnerable to resistance. Researchers used extremely powerful imaging techniques to see, for the first time, exactly what happens between bacteria and antibiotics at the atomic level. They report their findings in two studies in the journal Nature. The work provides the most detailed view yet of an enzyme structure that is key to turning on the genes that make bacteria work, said Irina Artsimovitch, a co-author on both studies and an associate professor of microbiology at Ohio State University. Artsimovitch worked with Dmitry Vassylyev, the lead author of both studies and a professor of biochemistry and molecular biology at the University of Alabama at Birmingham. The two conducted the study with researchers from the University of Alabama at Birmingham , the University of Wisconsin-Madison and the University of Nebraska Medical Center. In the first study, the team found that they could create a detailed image of the elongation complex, a structure formed by RNA polymerase. RNA polymerase is the enzyme responsible for setting gene expression in motion, a process called transcription. Without a properly functioning RNA polymerase, a cell will die. "RNA polymerase spends most of its working hours as the elongation complex," Artsimovitch said. "The complex makes RNA's messages one step at a time, many thousands of times, until its completion. "This structure is important from a physiological point of view, not only for antibiotic design, but also because faults in the complex have been implicated in many diseases such as hereditary cancers." Artsimovitch and her colleagues used the bacterium Thermus thermophilus to run their experiments. While T. thermophilus won't make a human sick, the bacterium is widely used to gather structural information at the molecular level. The researchers first isolated the RNA polymerase from T. thermophilus. They then created an active elongation complex by mixing the enzyme with small molecules of DNA and RNA. This solution hardened into a crystal, which the researchers could then examine using an imaging technique called X-ray crystallography. X-ray crystallography let them create a computerized image showing the minute details of the elongation complex. In the second study, the team learned how the antibiotic streptolydigin blocks transcription. Streptolydigin has been around for several decades and the researchers already knew that this antibiotic stops RNA polymerase activity inside a cell. But they didn't know what controlled this mechanism. "We have to know what we're looking at -- and working with -- before it's possible to make a useful antibiotic," Artsimovitch said. "Now we can. Now we can see where the enzyme and antibiotic make contact at the atomic level." Upon examining the X-ray images, the researchers found that the antibiotic prevented the normal operation of the elongation complex by freezing it in the inactive state. They saw a loop-shaped element that must close every time the elongation complex adds a nucleotide (a building block of DNA or RNA) to the growing RNA chain. This loop must open again to allow the next cycle to happen. If something such as an antibiotic keeps the loop from closing, RNA polymerase can't properly function and stalls. "This loop is a target for antibiotics, including streptolydigin," Artsimovitch said. "If we can design new drugs that will prevent its movements, then we will immediately stop the action of RNA polymerase, and bacteria will die soon thereafter." The team's findings may be applicable to realms outside microbiology and drug discovery. Such a clear picture of the RNA polymerase elongation complex may be useful to a number of research areas, including manipulating the complex to increase the efficiency of bacteria that can harvest biofuels, Artsimovitch said. "We think that this mobile loop is a hot spot for regulating transcription in all living organisms, not only by using antibiotics but also by manipulating cellular factors," she said.

Foreclosure’s building problem

She wasn't an investor. She didn't have a subprime mortgage. But when Jordan Fogal's house became uninhabitable, the 62-year-old grandmother says foreclosure became her best alternative.
Fogal's troubles began when she and her 72-year-old husband, Bob, moved to a new housing development near Houston in 2002. That first night in the new house, the dining room ceiling collapsed. Bob had pulled the plug in the Jacuzzi tub upstairs, and 100 gallons of water came crashing through the ceiling downstairs because the plumbing drains were not connected.
"That was a preview of coming attractions," Fogal says. Later, the roof and windows leaked, the yard flooded, the shower walls started bowing out, the floor in the kitchen started sinking, and mold began to grow all over the house. The smell was terrible, she recalls, and eventually Fogal's doctor ordered her to leave the house because of the dangerous mold levels. A construction company hired by the Fogals estimated that it would take $150,000 to repair everything. "I could afford my mortgage payment, but I couldn't afford $150,000 in repairs," says Fogal, who had a 30-year fixed-rate mortgage at the time. The home — appraised at $408,000 the day the couple bought it — ended up selling for $234,000 at a foreclosure auction.
"All of this time, I was begging the builder to fix these problems," Fogal recalls. But, she says, they only showed up to about 25% of the appointments she made. "That's absolute nonsense," says Tom Thibodeau, president of Tremont Homes and then-president of the Fogal home's builder, Tremont Custom Construction. "We tried everything we could to fix this house, and she refused it. She only wanted us to buy the house back."
The only original problem with the Fogals' house, Thibodeau says, was a roof leak that was neglected and led to a myriad of other problems. "She would like everyone to believe the house was foreclosed on because of the defect," he says. "But by neglect, she let the leak go and other problems manifested from the leak."
More than a subprime problem?Fogal's case is not an isolated incident. Greg Cole, a homeowner in Georgia who runs a gripe site at georgiamoldhome.com, says he is on the brink of foreclosure after dealing with structural problems and leaks that have led to elevated mold levels. He, his wife, and his two children now take antibiotics every day, he says, because of the high level of mycotoxins — a toxin produced by fungi — in their blood. Elizabeth Dziedzic, a Realtor in Orange Park, Fla., says the deficiencies in her home make it impossible to sell for the amount it would take to pay off her mortgage balance. "There are only few events that are as devastating to a family as the loss of the family home to foreclosure," she says. "I guess this would be a price my family will pay for trying to achieve the American dream."
Foreclosures are up 93% from last year, according to Irvine, Calif.-based Web site RealtyTrac. At the same time, questions are arising as to whether construction quality suffered as homebuilders worked at lightning-fast speed to keep up with demand during the housing boom. It has become increasingly common for homeowners across the U.S. to share personal stories about defective construction through Web sites and blogs.
Everything you read says that the rise in foreclosure has to due with subprime lending," says Nancy Seats, president of Homeowners Against Deficient Dwellings, a nonprofit consumer protection group for homeowners dealing with defective construction. "But [defective construction] absolutely has something to due with the rise in foreclosures. There were absolutely investors that pushed up the price of housing, but there is no question that there are home buyers that were taken in and scammed big-time."
Why not just sue your builder when an irreparable problem arises? Homeowners usually don't have the right to. Most new-home sales contracts state that the customer must go through arbitration before they can even think about bringing their complaint to court.

"Wait-And-See" Approach For Treating Ear Infections Substantially Reduces Use Of Antibiotics

For children with acute ear infections seen in an emergency department, giving parents the option of delaying use of antibiotics resulted in significantly lower use of antibiotics compared to parents who received a standard prescription, with little difference in the outcomes for the children, according to a study in the September 13 issue of JAMA. Acute otitis media (AOM; ear infection) is the most common reason for which an antibiotic is prescribed to children. Treatment of AOM accounts for an estimated 15 million antibiotic prescriptions written per year in the United States, according to background information in the article. Untreated AOM has a high rate of natural resolution, with similar rates of complications whether antibiotics are prescribed or withheld. Resistance to antibiotics is a major public health concern worldwide and is associated with the widespread use of antibiotics. David M. Spiro, M.D., M.P.H., formerly of the Yale University School of Medicine, New Haven, Conn., and colleagues conducted a study to determine whether treatment of AOM using a "wait-and-see prescription" (WASP) significantly reduced use of antibiotics compared with a "standard prescription" (SP), and evaluated the effects of this intervention on clinical symptoms and adverse outcomes. Overall, 283 children with AOM aged 6 months to 12 years seen in an emergency department were randomly assigned to receive either a WASP (n = 138) or a SP (n = 145). All patients received ibuprofen and ear analgesic drops for use at home. Phone interviews were conducted after enrollment to determine outcomes. The trial was conducted between July 2004 and July 2005. The researchers found that the WASP significantly reduced the use of antibiotics. Substantially more parents in the WASP group did not fill the antibiotic prescription, compared to the SP group (62 percent vs. 13 percent). There was no statistically significant difference between the groups in the frequency of subsequent fever, otalgia (ear ache), or unscheduled visits for medical care. The patients in the WASP group whose parents filled the prescription reported they did so because of fever (60 percent), otalgia (34 percent), or fussy behavior (6 percent). No serious adverse events were reported for patients in the study. "This randomized controlled trial has provided evidence that the WASP strategy significantly reduces the use of antibiotics in an urban population presenting to an emergency department and may be an alternative to routine treatment of AOM with antibiotics. Wait-and-see prescriptions remain controversial as most pediatricians in the United States have been trained to routinely prescribe antibiotics for AOM and believe that many parents expect a prescription; a small minority of practitioners who care for children routinely use watchful waiting. "The WASP approach may interrupt the cycle of antibiotic prescription, the expectation of parents to immediately treat AOM with an antibiotic, and subsequent medical visits for this illness. The risks of antibiotics, including gastrointestinal symptoms, allergic reactions, and accelerated resistance to bacterial pathogens must be weighed against their benefits for an illness that, for the most part, is self limited. The routine use of WASP for AOM will reduce both the costs and adverse effects associated with antibiotic treatment and should reduce selective pressure for organisms resistant to commonly used antimicrobials," the authors conclude.

Research May Lead To New Classes Of Antibiotics

Scientists have what could be some very bad news for disease-causing bacteria. All three major classes of antibiotics that kill infectious bacteria do so in part by ramping up the production of harmful free radicals, researchers report in Cell a publication of Cell Press. Because those different types of antibiotics each initially hit different targets, it had been believed they worked by independent means. The findings could point the way to new classes of antibiotics and to a common method by which existing antibiotics could be made to stamp out bacteria even better, according to the Boston University researchers. Such advances are particularly critical at a time when, according to the Centers for Disease Control and Prevention, nearly all significant bacterial infections in the world are becoming resistant to the most commonly prescribed antibiotic treatments. "Hydroxyl radicals damage DNA, which turns on the S.O.S. repair response," said James Collins. "Therefore, our findings suggest that if you could shut off the bacteria's repair response, you might make all bactericidal antibiotics more effective and effective at lower doses. You could in essence create a super-Cipro, super-mycins, and so on." Current antimicrobial therapies fall into two general categories: (1) bactericidal drugs, which kill bacteria with almost complete efficiency, and (2) bacteriostatic drugs, which inhibit their growth, allowing the immune system to clear the infection, Collins's group explained. The targets of bactericidal antibiotics are well studied and predominantly fall into three classes: (1) those that hit DNA, (2) those that hit proteins, and (3) those that hit the bacterial cell wall. In contrast, most bacteriostatic drugs work by blocking the function of ribosomes, which are the sites of protein synthesis. While antibiotics' ability to kill bacteria had been attributed solely to those class-specific drug-target interactions, "our understanding of many of the bacterial responses that occur as a consequence of the primary drug-target interaction remains incomplete," the researchers said. Collins and his colleagues recently uncovered some evidence that at least some antibiotics might have some other deadly tricks. They showed that one type of antibiotics, including quinolones, which block DNA's replication and transcription into messenger RNA, also causes a breakdown that leads to the production of free radicals. Moreover, they found that those highly reactive chemicals help finish the bacteria off. In the new study, the researchers wanted to know whether other antibiotics also drive the toxic brew. Indeed, they show, drugs that kill bacteria all do cause a rise in free radicals, and all in the same manner. This is not so for drugs that only stunt bacteria's growth, they report. "The ever-increasing prevalence of antibiotic-resistant strains has made it critical that we develop novel, more effective means of killing bacteria," the researchers concluded. "Our results indicate that targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response… is a viable means of potentiating all three major classes of bactericidal drugs. Moreover, pathway analyses and systems biology approaches may uncover druggable targets for stimulating hydroxyl radical formation, which could result in new classes of bactericidal antibiotics."

Industry Provides Antibiotics, Heart Medicines And Painkillers Needed In Lebanon By Its Health Ministry, The WHO And NGOs

In rapid response to urgent medical needs in the Lebanon, the researchbased pharmaceutical industry has donated antibiotics, heart medicines, painkillers and other treatments. Ahead of the international donors' conference in Stockholm to raise funds to help the Lebanon, the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) today provided an overview of medical aid already furnished by its member companies. IFPMA Director General Dr. Harvey Bale said: "While the wholesale value of medicines donated by pharmaceutical companies for this latest Lebanese emergency is approaching USD 5 million, what is more significant is how quickly these products have been made available and that the donations were to meet the specific emergency demands of the Lebanese Ministry of Health, the World Health Organization and experienced non-governmental organizations operating in the region." Dr Bale continued: "Such a rapid response can only be achieved by working closely with the organizations on the ground, national governments and the WHO. Existing specialized pharmaceutical aid coordination organizations, notably Health Partners International of Canada, International Health Partnerships (UK), Partnerships for Quality Medicine Donations (USA) and TULIPE (France), have played an invaluable role in ensuring the speed and focus of the pharmaceutical industry's recent humanitarian aid effort in the Lebanon." The medicines provided by pharmaceutical companies for emergency use in the Lebanon include anesthetics, antibiotics, anticonvulsants, antidepressants, antidiarrheals, antifungals, antiinflammatories, antiretrovirals, heart medicines (antiarrhythmic, anticoagulant, anticholesterol, antiplatelet and hypertension treatments), laxatives, stomach medicines (beta-blockers and H2- antagonists), painkillers and tranquilizers. The donor companies involved include: AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Jansen-Cilag, Merck & Co., Novartis, Pfizer, Procter & Gamble, sanofi-aventis and Schering Plough. The International Federation of Pharmaceutical Manufacturers & Associations is the global nonprofit NGO representing the research-based pharmaceutical, biotech and vaccine sectors. Its members comprise 26 leading international companies and 46 national and regional industry associations covering developed and developing countries. The industry's R&D pipeline contains hundreds of new medicines and vaccines being developed to address global disease threats, including cancer, heart disease, HIV/AIDS and malaria. The IFPMA Clinical Trials Portal (http://www.ifpma.org/clinicaltrials) and IFPMA activities in Health Partnerships (http://www.ifpma.org) help make the industry's activities more transparent. The IFPMA strengthens patient safety by improving risk assessment of medicines and combating their counterfeiting. It also provides the secretariat for the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

Antibiotics Help Combat Dangerous Tropical Disease

An antibiotic which has long been used to fight infections of the respiratory tract and intestine also seems to be able to defeat the dangerous pathogens causing elephantiasis. This is proved by a study carried out by parasitologists from the University of Bonn together with colleagues from Hamburg, Liverpool and Tanzania. Their findings have been published in the prestigious medical journal The Lancet (vol. 365, May 2005). The disease has previously been usually incurable. The disease is triggered off by the bite of an infected mosquito: together with its anticoagulant the mosquito pumps threadworm larvae into its host's body. These gravitate towards the lymph nodes, where they grow into threadworms which may be up to ten centimetres long. The body reacts by producing inflammation which halts the flow of lymphatic fluid. The consequence of this is that arms, legs and genitals swell to monstrous proportions - hence the name elephantiasis. More than 120 million people worldwide are infected with the pathogen wuchereria bancrofti. Adult wuchereria worms have a lifespan of up to five years. During this time they produce millions of offspring, what are known as micro-filariae, each of them smaller than the full stop at the end of this sentence. If the host is bitten again by a mosquito, the micro-filariae are ingested together with the blood. Inside the insect they mature into infectious worm larvae, thereby completing the circle. 'Although the drugs currently in use kill the micro-filariae, they largely leave the adult worms unscathed,' Bonn parasitologist Professor Achim H?f explains. 'Due to the long lifespan of the wuchereria worms, therapy lasts several years, during which time the symptoms continue to persist.' What is more, the drugs may cause severe side-effects. De-worming the roundabout wayYet the threadworm, too, has a sub-tenant, and this may be its Achilles heel, since in each wuchereria worm there are specific bacteria which are absolutely indispensable to the parasite's survival. If these bacteria die, the parasite will also die sooner or later. 'This is why wuchereria is susceptible to antibiotics which are normally used against bacterial infections,' Professor H?f emphasises. One example is doxycyclin, which has been used for decades for infections of the respiratory tract and the gastro-intestinal tract. In their study the medical experts in Tanzania treated 72 male patients for eight weeks with doxycyclin or a placebo. Initially the patients' blood was swarming with micro-filariae: the researchers counted up to 1,300 of them per millilitre of blood. Eight months later they had almost completely disappeared; only in one patient were sporadic micro-filariae still detected. However, the proportion of micro-filariae also dropped in the placebo group - an effect which was probably due to the improved care given the test persons. Unlike the drugs in use up to now the antibiotic also killed off the adult worms. Fourteen months after being treated with doxycyclin the doctors were only able to detect the typical movements of the worms ('the dance of the filariae') on ultrasound in one in five patients. In the placebo group the rate was 89%. In the doxycyclin group the concentration of specific worm proteins in the blood fell by over half. Effective, cheap, few side-effects'The importance of these findings for therapy should not be underestimated,' Professor H?f emphasises. 'The mature worms are after all responsible for such symptoms of the disease as the extreme swelling of the limbs. In the past there was no effective and reliable method of combating them.' The effectiveness of the antibiotic might be even greater than what was measured: 'We cannot exclude the possibility that several patients became re-infected in the months following treatment with doxycyclin. It is therefore quite possible that all the worms were killed and the remaining 20% are the result of re-infection which would no longer occur if infection was effectively prevented. Doxycyclin has been used for many years and has only minor side-effects. However, in young children it may cause irreparable damage to the teeth and slow down growth of the bones. For this reason the antibiotic should not be used during pregnancy, either. For adolescents and adults, however, the drug is harmless. Moreover, it is comparatively cheap. 'Its biggest advantage is that it is already licensed for medical use,' Professor H?f points out. 'Elephantiasis hits the poor most of all. It is therefore not likely that the pharmaceuticals industry will develop completely new drugs.'

Antibiotic Resistant Bacteria In Poultry Could Threaten Human Health

A surprising finding by a team of University of Georgia scientists suggests that curbing the use of antibiotics on poultry farms will do little - if anything - to reduce rates of antibiotic resistant bacteria that have the potential to threaten human health. Dr. Margie Lee, professor in the UGA College of Veterinary Medicine, and her colleagues have found that chickens raised on antibiotic-free farms and even those raised under pristine laboratory conditions have high levels of bacteria that are resistant to common antibiotics. Her findings, published in the March issue of the journal Applied and Environmental Microbiology, suggest that poultry come to the farm harboring resistant bacteria, possibly acquired as they were developing in their eggs. "The resistances don't necessarily come from antibiotic use in the birds that we eat," Lee said, "so banning antibiotic use on the farm isn't going to help. You have to put in some work before that." Lee and her team sampled droppings from more than 140,000 birds under four different conditions: 1.) commercial flocks that had been given antibiotics; 2.) commercial flocks that had not been given antibiotics; 3.) flocks raised in a lab that had been given antibiotics; and 4.) flocks raised in a lab that had not been given antibiotics. The researchers examined levels of antibiotic resistance in normal intestinal bacteria that do not cause human illness and - in a companion study published in May in the same journal - also examined levels of drug resistant campylobacter bacteria, a common foodborne cause of diarrhea, cramping and abdominal pain. They found that even birds raised in the pristine laboratory conditions had levels of antibiotic resistance levels comparable to what was seen on farms that used antibiotics. Even when the levels were lower, Lee adds, they were still well above the reasonable comfort zone for antibiotic resistance - roughly five to 10 percent. Seventy-three percent of the bacteria from one flock in the antibiotic-free commercial group were resistant to the drug oxytetracycline, for example, while 90 percent were resistant to the drug in a commercial flock that used antibiotics. Ninety-seven percent were resistant in the experimental flock that was given antibiotics, while forty-seven percent were resistant in the experimental group that was not given antibiotics. Strikingly, they even found bacteria resistant to streptomycin, a common human antibiotic that is rarely used in poultry and was not used on the farms the researchers studied. Bacteria swap genes relatively easily, and Lee explained that the concern is that drug resistance genes from bacteria that infect poultry could be passed on to bacteria that cause human illness. With these resistance genes, human bacterial illness could become harder to treat. These concerns led the European Union to ban the use of antibiotics for growth promotion in chickens in 2006. In 2005, the U.S. Food and Drug Administration banned the use of the drug Baytril - the brand name for enrofloxacin, a fluoroquinolone antibiotic - in poultry, citing concerns that it could lead to resistance in human antibiotics such as Cipro, also a fluoroquinolone. Several advocacy groups are pushing for a more comprehensive animal antibiotic ban in the United States, but Lee said her research plus the evidence from the Baytril ban suggests that approach won't help. "They banned Baytril in 2005, and if you look at Baytril resistance in campylobacter now it's essentially unchanged," Lee said. In previous studies, Lee has tried to recreate experimentally conditions that should lead to the swapping of resistance genes among bacteria. Lee said these events - known as the horizontal transfer of genes - do occur, but they may not be as common as initially thought. What may be driving the antibiotic resistance that Lee has observed in her studies is what's known as vertical transfer - from parent to child - of bacteria carrying resistance genes. In short, the birds may come to the farm harboring antibiotic resistant bacteria. "This issue of antibiotic resistance is more complicated than once thought," Lee said. "These findings suggest that banning antibiotics at the farm level may not be as effective as assumed. We need further studies to identify which management practice would be effective" Lee stresses that for consumers, the advice on poultry is the same that it's always been. Cook meat thoroughly and use proper food handling and preparation techniques - washing your hands regularly and keeping other foods away from raw chicken, for example - to minimize the risk of illness. "All foods have the potential to contain pathogens - all of them," Lee said. "There's no substitute for good food handling and preparation."