Friday, October 14, 2011

Development of new antimicrobial agents

Over the last two decades the flow of new antibacterial drugs into the market has slowed, leaving a frequent gap between diagnosis of resistant pathogens and effective treatment options. Coupled with the rise of challenging infections, such as those caused by hospital- and community-acquired MRSA or MDR Gram-negative bacteria, this situation is of increasing concern to clinicians (Arias and Murray, 2009).
A sad fact is that antibacterial compounds are unlikely to provide the financial incentives that attract large pharmaceutical companies. New agents released will have to compete with current agents that remain effective and they are likely to be held back as a last resort until overwhelming resistance develops. As a result the money invested in drug development is unlikely to be recouped until well into the future (Spratt and Wade, 2005).
Many large pharmaceutical companies have terminated their antibacterial research programs as they focus on potentially more lucrative therapeutic areas. At the same time, an increasingly dry funding situation obstructs smaller start-up companies (Theuretzbacher, 2009).
Whilst not taken seriously a few years ago, the situation is now ripe for innovative treatments such as monoclonal antibodies, therapeutic vaccines and phage formulations. Many of these activities are in an early phase of discovery and will not be available for testing in clinical trials for a few more years (Theuretzbacher, 2009).
Also there is a group of compounds termed ‘non-antibiotics’ exhibits properties that render them important for the therapy of MDR infections examples for these compounds are enzyme inhibitors, anti-plasmid therapeutics and efflux pumps' inhibitors. Non-antibiotics are at this time best considered as ‘helper compounds’ to be co-administered with conventional antibiotics to which the MDR organism was initially resistant (Martins et al., 2008).

*Monoclonal antibody-based therapies for microbial diseases:
Serum therapy by definition uses immune sera-derived immunoglobulins that are polyclonal preparations consisting of many types of antibodies of which only a minute fraction is specific for the intended microbe. In contrast, monoclonal antibody (mAb) preparations consist of one type of immunoglobulin with a defined specificity and a single isotype (Saylor et al., 2009).
Antibody therapies were the first effective antimicrobials used against infectious diseases. In the early 20th century serum therapy was used against a diverse range of infectious diseases, including pneumococcal pneumonia, meningococcal meningitis, erysipelas, anthrax and others. Unfortunately, the immunological complications associated with the use of heterologous sera in humans, such as serum sickness and immediate hypersensitivity, significantly limited its usefulness (Casadevall and Scharff, 1995).
Technological developments, such as improved purification techniques and the ability to engineer humanized mAbs, have greatly reduced these complications, allowed for increased specificity and expanded the range of possible targets (Saylor et al., 2009).
mAbs have direct and indirect antimicrobial mechanisms of action. Direct mechanisms include neutralizing toxins or binding to viruses to prevent host cell entry. Recently mAbs have also been shown to be directly bactericidal (LaRocca et al., 2008).
Indirect mechanisms involve Fc-mediated functions, such as modulation of the inflammatory response, promoting opsonic phagocytosis, and enhancing complement-mediated effects. This wide array of functions makes mAbs potentially useful against a variety of infectious diseases (Saylor et al., 2009).
Despite its current underdevelopment, the potential of antibody therapy in the form of mAbs is vast, especially for combating microbes that are resistant to antibiotic therapy, for emerging viral diseases or for the organisms or toxins responsible for bioterrorist threats. It is believed that mAbs are well poised to be important reagents in a new age of antimicrobial therapy (Casadevall, 2009).
mAbs inherently have a high specificity for their target and, since microbes are generally antigenically distinct from humans, the cross-reactivity with host tissues is minimal. In contrast to antibiotics, which target both harmful microbes and the host flora, mAbs will only target a specific microbe and their systemic administration should not affect other resident beneficial microbes (Saylor et al., 2009).
Microbial specificity means that mAbs are unlikely to select for drug-resistant microbes among non targeted microbes. The ability to specifically target disease-causing microbial populations without selecting for resistance makes mAb therapy potentially superior to broad-spectrum antibiotics that are generally used in therapy, at least for microbial diseases caused by single microbes (Kozyrskyj et al., 2007).

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