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Slaying Superbugs

Teaming up to fight drug-resistant bacteria

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ENG graduate student Michael Kohanski (left) and Jim Collins, an ENG professor of biomedical engineering and a Howard Hughes Medical Institute investigator. Photo by Vernon Doucette

The superbugs are coming — and not in the realm of Steven Spielberg.

Bacterial infections are outrunning some of the antibiotics designed to kill them. For example, one infamous superbug, methicillin-resistant Staphylococcus aureus, once found only in hospitals, has spread into schools and gyms. It infects about 100,000 people annually and contributes to almost 20,000 deaths in the United States, according to the Centers for Disease Control.

“With the growing emergence of antibiotic resistance, many of our drug therapies are increasingly ineffective,” says Jim Collins, a College of Engineering professor of biomedical engineering and a Howard Hughes Medical Institute investigator.

Bacteria are the ultimate survivors, fighting back guerrilla-style against the army of drugs designed to destroy them. They mutate into drug-resistant superbugs when antibiotics are needlessly prescribed, pumped into livestock on factory farms, or when patients don’t finish the antibiotics they’ve been prescribed.

At the same time, high risk and low profits slow the development of new, more effective bacteria-killing drugs.

So Collins teamed up with Timothy Lu, an M.D./Ph.D. student in the Harvard-MIT Division of Health Sciences and Technology, to give an old weapon for fighting bacterial infections some new ammunition: bacteriophages, viruses that infect and kill bacteria while leaving humans unharmed.

Doctors have used bacteriophages since the early 20th century, but they fell out of favor in the United States after the advent of powerful antibiotics. Now Collins and Lu have genetically modified a bacteriophage so that it zeroes in on a bacteria’s natural DNA repair mechanism, increasing the killing power of antibiotics and hindering the development of superbugs. Their findings appear in the March 2 online issue of the Proceedings of the National Academy of Sciences (PNAS).

“We were trying to find a new solution that would provide a more steady supply of antimicrobial therapies,” says lead author Lu. And in the race against superbugs, speed matters. Manipulating the DNA of a virus takes just a few weeks, rather than the years necessary to develop a new antibiotic.

“The harder part is selecting the right targets for the bacteriophage inside the bacteria,” says Lu. He and Collins chose to engineer their viruses to “overexpress” a protein called lexA3 that knocks out the bacteria’s DNA repair system, which would fend off an antibiotic.

The researchers tested their bacteriophage as an addition to three common antibiotics in test tubes of E. coli, and the combination killed about 30,000 times as many bacteria as the antibiotics alone. The dual therapy was also 1,000 times more effective against drug-resistant bacteria. When Lu and Collins moved on to experiments on mice, 80 percent of E. coli–infected mice treated with both a bacteriophage and an antibiotic survived, compared to 20 percent of mice receiving just antibiotics.

Bacteria will eventually develop resistance to a bacteriophage as well, Collins notes, but “resistance will develop more slowly in a combination therapy.” In a never-ending arms race against superbugs, researchers say, a “library” of bacteriophages engineered to attack bacteria in different ways will always be necessary.

Collins is a scientific advisor for Novophage, a start-up company cofounded by Lu to market genetically engineered bacteriophage therapy for clinical care. The company is very young; its business plan is currently entered in several university competitions, including one sponsored by BU’s Institute for Technology Entrepreneurship and Commercialization.

Chris Berdik can be reached at cberdik@bu.edu.

4 Comments

4 Comments on Slaying Superbugs

  • Kadiyali M Srivatsa on 03.23.2009 at 2:41 am

    We Need Help

    I think we must sit outside the box and take a closer look at how to handle this threat. Trying to kill the bacteria is like invading Iraq, we will have more problem than what we anticipate. Phage therapy may be one solution but I feel we must form a group of lateral thinkers to solve the riddle.
    Best Wishes to your project.

  • Anonymous on 03.23.2009 at 5:36 pm

    darn Evolution!

    The problem with any kind of anti-microbial treatment is that we play right into natural selection. The bacteria that survive the attack have some sort of resistence, and so can survive to produce more of themselves and eventually they all just feed off of penicillin or whatever we use to kill them.

    There’s never going to be an end-all quick fix, but that doesn’t mean we shouldn’t keep changing and adapting. In the mean time, I think people need to be educated about prevention and proper body care, so that even before they get sick they are at least a little bit more resistent to infection.

    There’s a story about a doctor who became very famous, and people would come up to him and say, You are the best doctor in the land! He replied, no, I take a year to cure my patients, there is an even better doctor than I.

    They went to the second doctor, and he said, I cure my patients in a couple of months, there is an even better doctor than I.

    And so they came to the third doctor, and they said, “we have heard you are the best doctor, that you cure illnesses just as they start!” The doctor shook his head and replied, “yes, but there is an even better doctor who gets no attention or fame, although he has the ability to destroy illness before it even starts!”

    We should be striving to create more of those kinds of doctors, who know how to get people to take care of themselves consistently so that they are healthier in their daily lives and thus get sick much, much less!

  • Anonymous on 03.24.2009 at 1:27 pm

    The history of technology shows that technological solutions are both developed and used in a ‘systems’ approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    This is a valid technological advance, likely to be more effective within the systems we use to manage disease. As the article alludes, This technological advance is required to keep the current solution system to fighting bacteria affloat. as the respondes rightly acknowledge, the solution system we are employing to manage bacterial infection is unstable and ripe for a catastrophic collapse.
    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
    We MUST think outside the box because it is common knowledge that the box doesn’t work. What is also common knowledge is that the main failure of the system is THE INAPPROPRIATE USE of antibiotic technology. The weak links appear to be patient compliance and inappropriate prescriptions by doctors.
    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
    Patient compliance will always be difficult. History shows us that patient compliance, must sometimes be enforced with imprisonment (Tuberculosis) and soldiers (plague/ scarlet fever) The decision to enforce patient compliance has always been a political cost/benefit decision. Apparently 20,000 deaths per year (still less than automobiles) is not yet enough of a crisis to enforce compliance.
    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
    Inappropriate prescriptions by doctors is a much easier system change to make. The doctors make individual choices based on factors such as fear of malpractice and wanting to provide the appearance of ‘doing something’ when the best decision would be to do nothing. I find it AMAZING that doctors are encouraged to commit malpractice to avoid claims of malpractice. First do no harm, is being violated
    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
    Until doctors are charged with the harm they cause by inappropriate prescription, I believe the system for combating bacteria will continue to fail.
    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
    Congratulations for the technological achievement. Now lets hope medical politicans can fix the main problem here: the ‘people problem’ in wasting our technological arsenal on fighting the wrong bugs in the wrong places. The analogy to Iraq was spot on.
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  • Bill on 03.24.2009 at 8:00 pm

    Superbugs and phage therapy

    I think that the state of actual phage therapy needs to be described – here is a short summary of where phage therapy is today:

    Choosing to let patients with superbug infections die rather than phage them!
    In Canada the official body counters tell us that “an estimated 220,000 patients who walk through the doors of hospitals each year suffer the unintended and often devastating consequences of an infection” and they also estimate that 8,000 to 12,000 Canadian patients die annually from such infections. In the USA the Centers for Disease Control and Prevention reports that methicillin-resistant Staphylococcus aureus seriously sickened more than 94,000 Americans in 2005 and almost 19,000 died, more than the 17,000 Americans who died of AIDS-related causes.

    However, the joke is on us because the French-Canadian microbiologist, Felix d’Herelle, discovered phage therapy in 1917. Phage therapy uses highly specific viruses, bacteriophages, which have been observed to be harmless for humans, to treat bacterial infections, including infections caused by superbugs. While there is considerable expertise on phage therapy in Canada and the USA at the research level, medical phage therapy is not currently approved or practised in Canada; however, it can be made available legally to Canadian patients under the Special Access Program of our Food & Drugs Act! There are moral and ethical reasons for making phage therapy available in countries that are members of The World Medical Association which states: “In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician’s judgement it offers hope of saving life.” A recent paper in English from Poland entitled: “Phage therapy of staphylococcal infections (including MRSA) may be less expensive than antibiotics (2007)” could serve as a model for the introduction of phage therapy in North America since our laws appear similar to those described for Poland ( paper can be found at http://www.gangagen.com/newsroomframe.htm ).

    A discussion of phage therapy is currently very timely, not only because too many patients are dying of superbug infections; but also because of the recent release of the Canadian film: Killer Cure: The Amazing Adventures of Bacteriophage and the June 2006 release of the book by Thomas Haeusler entitled, Viruses vs. Superbugs, a solution to the antibiotics crisis? ( see http://www.bacteriophagetherapy.info ). There is a record of an excellent questions-and-answers session on phage therapy with Dr. Roger Johnson of the Public Health Agency of Canada at ttp://meristem.com/topstories/ts06_08.html .

    Further, the phage therapy file has dramatically changed because the US Food and Drug Administration (FDA) has amended the US food additive regulations to provide for the safe use of a bacteriophage preparation on ready-to-eat meat and poultry products as an antimicrobial agent against Listeria monocytogenes (see http://www.fda.gov/OHRMS/DOCKETS/98fr/02f-0316-nfr0001.pdf ). An enlightening FDA questions-and-answers document can be found at http://www.cfsan.fda.gov/~dms/opabacqa.html . Listeria causes an estimated 2,500 cases of mainly food borne infections in the USA annually and as many as 500 deaths; however, the idea that ready-to-eat meat can be treated, if contaminated with Listeria bacteria, while a doctor could not get a pharmaceutical grade phage therapy product when faced with a patient suffering listeriosis strikes this author as absurd. Superbugs should be of interest to everybody because sooner or later everybody will be faced with an infection or know someone who will be suffering or dying with one. Withholding such treatment from patients when antibiotics are failing ought to be a crime; however, those who have the money, knowledge and time to travel when faced with an infection where antibiotics are failing may be able to get phage therapy treatment in Georgia , Europe ( http://www.phagetherapycenter.com ), Poland – http://www.aite.wroclaw.pl/phages/phages.html or more recently at the Wound Care Center, Lubbock, Texas ( http://www.woundcarecenter.net/ ) .

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