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    Antibiotic Compounds That Bacteria Can't Resist
    By Hayley Mann | March 13th 2009 02:29 PM | 5 comments | Print | E-mail | Track Comments
    About Hayley

    In 2006, I graduated from UC Davis with a degree in Genetics and Anthropology. I've had the privilege of working for various laboratories conducting...

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    The increasing frequency of bacterial resistance to antibiotics is alarming.  Researchers from the Albert Einstein College of Medicine of Yeshiva University believe they may have found a solution to this seemingly losing battle.  Professor Vern L. Schramm and team have developed antibiotic compounds that do not lead to microbial resistance over time.

    Administered antibiotics initially work extremely well, killing more than 99.9% of the microbes they target.  However, microbes have a high rate of mutation and because antibiotics are initially designed for a single specific target, they are unable to kill 100% of microbes during an infection.  The surviving microbes that have successfully avoided antibiotics continue to replicate and spread, leading to new antibiotic resistant strains over time.

    Dr. Schramm hypothesized that antibiotics do not necessarily have to kill the microbe itself, but rather, disrupt their infectious nature.  In other words, if the microbe survives but does not replicate, then resistance to antibiotics will not occur.

    In the Nature of Chemical Biology study, test microbes Vibrio cholerae, which causes cholera, and E. coli strain 0157:H7, the notorious food contaminant responsible for ~110,000 illnesses each year in the U.S. were used.  The aim of the research study was to disrupt the infectious microbes' ability to communicate with each other. 

    The process by which bacteria communicate is called "quorum sensing."  In quorum sensing, signaling molecules known as "autoinducers" are detected between bacteria.  These autoinducers regulate expression of bacterial genes, including genes associated with virulence.  Previous studies have shown that bacterial strains defective in quorum sensing are less infectious.

    The bacterial enzyme "MTAN" is directly involved in synthesizing autoinducers and is crucial in catalyzing quorum sensing.  The team's aim was to inhibit MTAN by designing a substrate to which the enzyme would preferentially bind to as opposed to its human host substrate. 

    In order to design an analog of MTAN's natural substrate, the Schramm lab obtained a picture of the enzyme's structure during its brief transitional state period (one-tenth of one trillionth of a second) in which the enzyme converts its substrate into a different chemical. 

    With knowledge of the enzyme's transitional structure, Dr. Schramm and his colleagues constructed and tested three MTAN transition state analogs.  All three compounds developed were highly successful in disrupting the quorum sensing pathway in both V. cholerae and E. coli 0157:H7.  Not only did MTAN preferentially bind to Schramm's analogs, but in fact, the analogs permanently inhibited the enzyme from initiating quorum sensing.

    To test if the microbes would develop resistance over time, the researchers tested the analogs on 26 successive generations of both bacterial species.  All 26 generations were as sensitive to the antibiotics as the first generation was.

    "In our lab, we call these agents everlasting antibiotics," said Dr. Schramm. 

    Dr. Schramm also points out that many aggressive bacterial pathogens express MTAN and therefore would probably also be susceptible to these inhibiting analogs including: S. pneumoniae, Klebsiella pneumoniae, N. meningitides, and Staphylococcus aureus.

    To date, Schramm's research team has developed more than 20 highly effective MTAN inhibitors, all of which are expected to be safe for human usage since MTAN is a bacterial enzyme and blocking it would have no effect on human metabolism.

    The study, "Transition State Analogs of 5'-Methylthioadenosine Nucleosidase Disrupt Quorum Sensing" was published in the March 8, 2009 online edition of Nature Chemical Biology.

    Comments

    Thank you for your post on this work. I had not encountered any other coverage of the topic before yours, and it is a very interesting subject. Did you get to see the article from the Nature Chemical Biology web site--or otherwise--or pick-up of the College of Medicine's press' news release? For clarification, Ruth Merns was not an author of the study. Vern Schramm's title is "Professor and Ruth Merns Chair of Biochemistry."

    Alternate Allele
    Found this study as a press release (I fixed the title mistake, thanks for pointing that out). 

    I am surprised that no one else has covered this topic considering anti-biotic resistance is something the majority of the general populous has thought or heard about; clearly individuals that scan press releases have not recognized the significance of this study.  I for one am glad to hear that there is some promising research being conducted to fix this rather scary issue of microbial resistance.  And really, this study is a fascinating approach considering it could most likely be applied for any harmful microbe.
    Oh, how exiting that a quorum sensing antibiotic seems to be successful! Bassler's work has opened up so many new doors - thanks for the article!

    With medical institutional infections in particular, sometimes death is a good thing- for a vicious multi-cellular organism.
    There are a variety of different types of bacterial infections one can get from many different sources, yet some locations are more common than others. If bacteria are not beneficial for your health, as many bacteria are, they should die in order to restore your health.
    Bacteria are a simple life form, yet are incredibly productive and efficient. As with other life forms, they exist to reproduce, and does so about every hour. Bacteria mutate, evolve, and adapt according to the host in which they exist.
    To do this, it fully utilizes all available resources and energy to develop the protein that is essential for its survival in their host. Bacteria need exactly 7 genes to produce the essential ribosomes for their existence. Any more or less genes than 7, the bacteria is not maximizing its efficiency to survive and reproduce. Amazing.
    Strep infections are caused by what are called gram positive bacteria, and they are the most common bacteria that infect other humans. . Group A strep infections can cause diseases such as strep throat and pneumonia. Also, staph bacterial infections are gram positive as well that potentially infect humans, and do so often.
    Of all pathogenic, or disease-causing bacteria that exist, it is the MRSA, the methicillin resistant staff aureus bacteria, that are most concerning to health care providers in particular. This is because MRSA bacterial infections are the most difficult to cure when a patient suffers from their damage from being infected by these bacteria.
    Another difficult situation is when a patient is infected by VRE, Vancomycin Resistant Enterococci, which is another type of gram positive bacteria that exist.
    These MRSA and VRE bacteria are difficult to eradicate due to the fact that most antibiotics that are available to rid the patient of other bacterial infections, MRSA and VRE are resistant to the effectiveness of these antibiotics.
    MRSA and VRE infected patients are quite challenging for the health care provider who is attempting to cure patients infected with these particular bacterial infections.
    In many situations, pathogenic bacteria infect a patient already within a medical institution for another disease. When this occurs, it is called a nosocomial infection.
    Greater than 5 percent of nosocomial infections are determined to be MRSA infections, it has been reported. As a result, there are about 100,000 serious hospital infections, as well as about 20,000 deaths from MRSA infections annually.
    Since there are several types of pathogenic bacteria that exist, a diagnostic test called a culture and sensitivity is usually performed at a clinical laboratory to assure the correct antibiotic is selected for treatment, as the bacteria are identified with this diagnostic method.
    Typically, fluid from the area suspected of being infected is obtained from the patient suspected to have an infection and smeared on what is called a petrie dish. And then these dishes are incubated for 2 to 3 days. Gram positive bacteria stain during this process a dark violet or blue. Gram negative bacteria would be pink in color, and are capable of harm as well to a human being.
    When the culture is complete, technology that is available offers recommendations on the appropriate class or brand of antibiotic to treat the pathogenic bacteria present in another person- presuming the bacteria will not be resistant to the antibiotic recommended, as this happens on occasion.
    Usually, classes of antibiotics that are used to treat gram positive strep infections that are not VRE or MRSA bacteria are cephalosporins, macrolides, or general penicillins. If the microbe that is causing the infection is resistant to the antibiotic from such classes that are administered to the infected patient, other options should be considered for anti-microbial therapy.
    With two very powerful antibiotics in particular, which are methicillin and vancomycin, their frequent use in infected patients has resulted in VRE and MRSA bacteria that are now resistant to these antibiotics.
    When a patient is infected with VRE or MRSA bacteria, other selections for antimicrobial therapy that provide more efficacy should be selected for a patient infected with these types of infections. Such brands and types of antibiotics for MRSA and VRE bacteria include Zyvox, which has both IV and oral dosage options, and an antibiotic called Cubicin.
    However these antibiotics for antibiotic resistant bacteria are given usually due to infections that have progressed to a more serious nature within a patient infected in such a way, so a cure is not immediate when these antibiotics are selected for such patients.
    Progressive medical conditions with such infected patients include sepsis, or blood infection, osteomyelitis, or bone infection, as well as pneumonia, which is a serious lung infection. A hospital stay is normally required with such patients infected with MRSA and VRE infections that cause such diseases.
    This is because when the antibiotics that potentially cure the patient of these microbes are selected, they are usually given via IV administration, and are administered normally for several days, if not several weeks.
    There are numerous classes and types of antibiotics available, yet bacterial resistance to most of these antibiotics, with the exception of the two mentioned earlier, constantly remain a serious concern for the health care provider, and the MRSA and VRE infected patient.
    With MRSA at the top of the list of concerns for the health care providers, this infection continue to occur progressively, which amplifies the concerns of others.
    Medical institutions should possibly consider quarantine for those patients at their locations that have been determined to be infected with the MRSA and VRE bacteria more often in the future.
    http://www.cdc.gov/ncidod/dhqp/ar_mrsa_spotlight_2006.html
    Dan Abshear

    vonankh
    Thanks for enlightening article and comments!