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March 15, 2009 (Vol. 29, No. 6)

Combating Hospital-Acquired Infections

Significant Opportunity Exists for Innovative Biopharmaceutical Companies

  • Opportunity for Biotech

    Despite the need, HAIs do not seem to be a priority for large pharmaceutical companies. In 2007, the FDA approved 74 new therapeutics, of these, two were antibiotics—one a topical ointment for the treatment of impetigo and the other an intravenous drug for the treatment of complicated intra-abdominal and urinary tract infections.

    Only about 50 of the more than 2,700 compounds currently in development are being developed as bacterial antibiotics.  Significantly, only 20% of these projects, a total of 10 out of 50 are being undertaken by large pharmaceutical firms. 

    Why isn’t Big Pharma responding? It’s a fair question to ask. It could be that there is no potential for a blockbuster drug in this application, as the frequency of resistance makes it a difficult area to commit to long-term product investment. Therefore, as a result of the low priority such products have in traditional pharma, we believe the most logical player is the the biopharmaceutical community.

    One option for the therapeutic community is to somehow silence drug-resistance genes. There is the possibility that some molecular method may be devised that will affect the genes of a bacterium preventing its reproduction, but this may be more expensive than other approaches. It will also require determining the relevant genes and empirically ascertaining which may be the most effective in eliminating the bacterial infection. In addition, it may be a possibility to restore drug sensitivity to bacteria in vivo.

    If a bacterium is resistant to one class of antibiotic, it will readily develop resistance to all, or almost all, of the antibiotics in that chemical class. This means that the cause of the drug class resistance may be a single gene or it may be a family of closely related genes. If this is the case, and it likely is, it may be possible to silence the responsible gene(s). This could be done via antisense, siRNA, or other nucleic acid-based therapeutics technologies.

    Rapid diagnostic tests would then, determine the specific resistance of a bacterial strain. A combination or a sequential administration, of silencing agents and antibiotics could provide the necessary conditions for effective treatment of the infection, and it could breathe new life into the tired and often ineffective antibiotics now on the market.

    One problem, however, is that biotechnological therapeutics tend to be expensive. Compared to penicillin, their purchase is akin to the difference between purchasing a Rolls Royce and a Chevrolet. Even among some of the most expensive antibiotics, such as vancomycin, this is the case. How, then, can these new technologies address the problems of drug-resistant nosocomial and other infections?

    It is clear that the solution lies in small molecules. For example, the development of recombinant human antibodies to bacterial strains is far too expensive. On the other hand, smaller molecules, such as small nucleic acid-based compounds or combinations of these compounds, may be the answer. Single molecules that address the silencing of a gene may need to be too large to penetrate the bacterial wall.

    Combinations of smaller polynucleotides, addressing different and complementary portions of the bacterial genes may be made to enter the bacterial wall and silence the bacterium’s genetic resistance mechanisms or reproductive mechanisms. Such therapeutics may be somewhat more expensive than current antibiotics, but at the same time, their utility may be far greater.

    Imagine that several strains of a particular species contain a similar, or possibly identical, reproductive sequence—not an impossibility and, in fact, highly probable.  If this is the case, then a series of neutralizing probes could be used to eliminate the pathogen by cutting off the reproductive mechanisms. 

    This presupposes a great deal of genetic knowledge about bacterial pathogens. It also presupposes that there are companies willing to take a chance on developing such unique antimicrobials for nosocomial and community infections. We believe this effort is far more likely to emerge from the innovators in biotechnology than in the pharmaceutical establishment.