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Drugs boost antibiotic function

Combining antibiotics with bioactive drug compounds can improve antibacterial activity, breathing new life into antibiotics weakened by growing bacterial resistance

By | April 25, 2011

The rise in antibiotic-resistant bacteria, along with the slowed rate of new antibiotic development, has prompted researchers to look for alternative therapies to fight disease-causing pathogens. New linkurl:research,;http://www.nature.com/nchembio/journal/vaop/ncurrent/abs/nchembio.559.html published yesterday (April 25) ahead-of-print in Nature Chemical Biology, provides evidence that combining antibiotics with marketed drug compounds could be one answer, uncovering previously unknown antibacterial functions of drugs that boost the effectiveness of antibiotics. "This is a really ingenious approach that, frankly, we need a lot more of," said linkurl:Christopher Graber,;http://dhaake.bol.ucla.edu/cjg.htm an infectious disease physician in the Greater Los Angeles Healthcare System who was not involved in the research. "It opens up a whole new field of combining antibiotics with non-antibiotics," agreed Mark Riddle, a research medical officer at the linkurl:Naval Medical Research Center's Enteric Diseases Department;http://www.med.navy.mil/sites/nmrc/Pages/id_ed.htm who was not involved with the research. "I would think that this paper is going to get a lot of conversations started."
A cocktail of antibiotics and other drugs
Image: Flickr user emilybean
Antimicrobial resistance is on the rise, evidenced by greater use of "last resort" antibiotics such as vancomycin and recent epidemics of antibiotic-resistant diseases, including tuberculosis and MRSA. For decades, researchers and clinicians have been combining antibiotics to increase their efficacy against such resistant bacteria, but those obvious efforts don't go far enough, said linkurl:Gerry Wright,;http://www.science.mcmaster.ca/biochem/faculty/wright/ an antibiotic biochemist at McMaster University. Only considering other antibiotics is "too limiting," he said. "You need to cast the net a bit wider and look at other molecules that are bioactive and look for enhanced activity." So Wright and his colleagues decided to broaden the search. They focused on minocycline, an antibiotic that inhibits protein synthesis, frequently used in the 1950s and 1960s until bacteria developed resistance. "It seemed like a good place to start as something that already had some intrinsic anti-microbial activity but had been largely abandoned by the clinical community because of the resistance problem," said Wright. They screened minocycline in combination with more than 1,000 previously approved bioactive drug compounds -- most of which had no known antibiotic function -- against three common and often resistant bacteria: Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus. The screen revealed a total of 69 compounds never before used to treat bacterial infections that, when combined with minocycline, decreased bacterial growth by at least 45 percent -- significantly more than when treated with only the antibiotic . "It was very gratifying for us that our hypothesis was right," said Wright. "We found all these unexpected interactions." One finding that surprised the researchers was that many of the compound combinations inhibited only one of the three bacteria species tested, suggesting that these could be used to target specific infectious bacteria and leave the rest of a patient's microbial flora alone. "There are a lot of bacteria that are quite good for us and if you kill off good bacteria, [infectious bacteria] can take over," said Graber. "You want to attack your offending organism with as narrow a possible a spectrum." The researchers further examined loperamide, an opioid anti-diarrheal agent marketed as Imodium, which inhibited 99 percent of P. aeruginosa and 70 percent of E. coli growth when combined with minocycline in the initial screen, though it had no antibacterial function on its own. They found that it disrupts the electron potential across bacterial membranes, effectively weakening the cell and giving the minocycline a way in. Riddle had previously found that treating diarrheal infections with a combination of loperamide and antibiotics resolved patients' symptoms significantly faster. He assumed that this was "likely due to the loperamide helping with the symptoms, while the antibiotics work[ed] on eradicating the infection," he said. "But this study opens up the... thinking that maybe there are some other mechanisms that it would have in synergizing with antibacterial drugs." Many questions remain, of course, such as how well the drug combinations will be absorbed by the body. But Wright is optimistic that finding new uses for old drugs will give less-effective antibiotics a second wind. "I hope that the work will make people realize that it's not hopeless and that we will find new ways to solve the resistance problem and the lack of new antibiotics problem," he said. "Instead of thinking one molecule at the time, we need to think about things in a much broader way and good things might come of it." L. Ejim et al., "Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy," Nature Chemical Biology, doi:10.1038/nchembio.559, 2011.
**__Related stories:__*** linkurl:Teaching an Old Drug New Tricks;http://www.the-scientist.com/article/display/58079/
[1st April 2011]*linkurl:Opinion: 5 ways to save antibiotics;http://www.the-scientist.com/news/display/57862/
[14th December 2010]*linkurl:Barriers on the Road to New Antibiotics;http://www.the-scientist.com/article/display/15318/
[14th March 2005]
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Comments

Avatar of: Jamie Caryl

Jamie Caryl

Posts: 4

April 25, 2011

I love the idea of minocyline combined with antabuse, as detailed in the paper; this would really put a dampener on the day of those poorly compliant patients who refuse not to drink on mino.

April 25, 2011

The article and described approach is very interesting one, though not completely original. Similar approach was used some fifty years ago with chemoterapeutics (e.g. sulpha drug sulfamethoxazole and trimethoprim).\n\nRegarding antimicrobial resistance two issues are critical in application of antibiotics:\n1. Antibiotic therapy should be applied long enough. Unfortunately, due to the exaggerated fear of adverse effects of antibiotic therapy, this is not everyday practice. Too short antibiotic therapy is global problem. \n2. New antibiotic (or antibiotic combination) should start its application as "last resort" drug and not as a drug for the infection of the upper respiratory tract (in order to enable such practice, intelectual property regulations should be changed, if necessary).\n\nFurthermore, it is the last moment to intensify research on new antibiotics or their combinations, because in their fight for survival, microorganisms do not care about pharmaceutical industry profits.\n
Avatar of: Vijay Nema

Vijay Nema

Posts: 1

April 25, 2011

Its the beginning of a great work that saves us reinventing the wheel when something is already there to help us. This work reminded me of an incident where my 1 year old cousin (now 24 years)was treated for severe diarrhoea by a traditional practitioner using pure opium. My cousin recovered miraculously and never had the same problem till date. \nThis also indicates that the rich wisdom of traditional medicine can provide us tools against the tough bugs and also other medical problems.\n

April 26, 2011

Dear Madame and Sirs\nSince the mid-70s, there has been ongoing research in an anti-bacterial resistance where psykofarmika included as a booster. This research has since the millennium was indicated by the international non-antibiotic research team led by among others Dr. Kristiansen, Jette E.\nThis international research team has heaviness of phenothiazines and clorpromazin - formerly used as antipsychotics - have been shown to neutralize multi-resistant bacteria. This discovery seems to have global humanitarian potential. See the article february in 'Advances in Enzymology' of Prof. AMARAL, Leonard. In addition see also the magazine 'Antiinfective Agents'.\nIn Mumbai a clinic has taken ? ?compassionate use? - the results from this group so fare for terminal TB- patients. It seems to be a success.
Avatar of: LISA HALL

LISA HALL

Posts: 12

April 28, 2011

Whatever happened to the research done years ago in Russia on using bacteria phages to fight bacterial infections? I remember reading that all you have to do is grow up a bunch of the pathogenic bacteria and since they always have their native ?predator? (the phage) with them in culture, you just purify out the bacterial virus and voila?you have a specific killer of the bacteria in question. Resistance was not an issue because as the bacteria mutate to avoid the phage, the phage mutates too. Humans didn?t have to redesign the antibacterial agent, the phage (and natural selection) did it on its own. These phages are also really specific for the particular bacteria, so killing the good ?native? bacteria was not a problem. As I remember the article saying however, a ?broad spectrum? phage ?antibiotic? was not easily accomplished because they were so specific. They were getting around this by pooling phages to hit a broader spectrum of bacteria. The article said that the Russian army was using it for their soldiers when they had to deploy them to places with nasty bacterial diseases.

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