viernes, 19 de julio de 2013

Potential MRSA Breakthrough and Antibiotic Economics

By: Tamara Johnson
May 16, 2013

A molecule found in breast milk may re-sensitize MRSA to antibiotics. This could be good news, especially considering the economic disincentives to develop new antibiotics.

Researchers at SUNY University at Buffalo recently published a paper finding that a molecule called HAMLET, purified from breast milk, may re-sensitize antibiotic resistant bacteria to already existing treatments. This is potentially very good news.

Bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA, or resistant staph) have evolved resistance to almost everything developed to combat infection. Studies place the number of MRSA-related deaths per year in the US at about 19,000. "The reason MRSA exists," says Maryn McKenna (@marynmck), author of the book Superbug: the Fatal Menace of MRSA, "is the failure of previous attempts to treat staph. Methicillin was the first of the class of semi-synthetic penicillins. They were developed in the 1960s because staph became resistant to penicillin just one year after that drug was released to market."

After methicillin came a series of "me too" drugs. These are so similar to methicillin in molecular structure that very slight adaptations were required for MRSA to develop further resistance. A drug called vancomycin was the next step in treatment options. "MRSA's response to that drug was quickly to evolve vancomycin resistant staph. There are two different sets of mutations—one is resistant and one is intermediately resistant. That brings us almost to the end of the available drugs," says McKenna.

So, if HAMLET can re-sensitize bacteria to already available treatments, it could be a literal life-saver. HAMLET is an adjuvant, an agent that modifies the effects of another agent. In this case, the modification increases antibiotic potency, though the exact mechanisms of the synergy are not yet known. It is known that HAMLET binds to hydrogen pumps in the cell membrane that create pH and energy gradients between the inside of a cell and its external environment. Disrupting these pumps interferes with a cell's ability to produce energy and, potentially, to expel antibiotics, but more research is required to understand the biochemistry involved, explains Dr. Hakansson, the Principal Investigator on the paper.

Given MRSA's relentless record of survival adaptations, the question immediately comes to mind: will the bacteria just develop resistance to HAMLET? According to Dr. Hakansson, while this is always a possibility, signs so far are positive. "It's very easy to make antibiotic resistant bacteria strains in the lab. You take a strain that is sensitive to methicillin, for example. Then you add your antibiotic at gradually-increasing concentrations over time and the let the bacteria adapt. We tried really hard to do this with HAMLET and haven't succeeded," he says. Hakansson hypothesizes that this has to do with the hydrogen pump to which HAMLET bonds. The pump is so essential to cell physiology that HAMLET-evasive mutations render the bacteria "extremely unfit."

HAMLET's adjuvant function may prove to be economically advantageous. Despite increasing concerns about resistance to current antibiotics, there isn't much work in the pharmaceutical industry on innovative treatments. Of seven new antibiotics in the pipeline, none utilize novel mechanisms. "There are only a few drugs left and they're not great," says McKenna. "It's a symptom of market failure."

A report by the President's Council of Advisors on Science and Technology describes economic disincentives behind the dearth of antimicrobial R&D. The cost of drug development has increased exponentially about every nine years since 1975. Approval for new treatments is far from guaranteed, and resistance development can take an antibiotic out of the market well before a profit can be made. Furthermore, truly new antibiotics are likely to be shelved to be used as "secret weapons" when other options fail. Dr. Hakansson is hopeful that work on HAMLET will be able to avoid, and even help counterbalance, these issues. "An adjuvant is great because you can use it with old antibiotics that are already well-characterized and known to be safe. There might be more of an interest in industry to develop this kind of agent."

Disclaimer: The views and opinions expressed in the articles on are those of the author(s) and do not necessarily reflect the views or opinions of the New York Academy of Sciences.

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