Extremely Narrow Spectrum Drugs

The often dramatic course of life-threatening infections, the lack of ultrarapid diagnostic methods to detect the causative agent(s), and, especially, the fact that the appropriateness ofthe first therapeutic agent chosen is decisive for the further course of the disease [42, 43] has led to a general need for very broad-spectrum antibiotics capable of attacking all important pathogens which might be causative of a certain infectious condition. An obvious drawback of such a broad-spectrum approach is the concomitant unavoidable attack on bacteria that are not responsible for the disease but are beneficial and important for our well-being. It should be kept in mind that most bacteria are, in fact, essential for us, and that we carry about a kilogram of such bacteria within our body (mostly in the gut). Furthermore, a broad-spectrum attack of this kind carries the risk of resistance development not only among the targeted pathogen(s) but also among many other species. However, at present, the market potential of narrow-spectrum drugs, which could be applied only after identification ofthe causative pathogen, is too small to warrant the investment necessary to develop them. Even for the most prevalent pathogens the cost of development would be clearly higher than the potential sales, given the present expectations for the price of antibiotics. A good example of this dilemma is provided by the so called pyrimidinones [87]. This class of antibiotics stems from a natural compound called TAN 1057, which was too toxic to be clinically useful and had a very narrow spectrum of gram-positive activity. Following a total synthesis approach, this class was optimized and resulted in a toxi-cologically safe derivative with outstanding, extremely bactericidal activity against two of the most pressing resistance problems in today's hospitals, MRSA and VRE. However, all attempts to expand its spectrum to include at least all other relevant gram-positive pathogens have failed so far, and the market potential of such a reserve drug was too low to warrant development. Thus, we cannot expect a narrow-spectrum approach to become reality until either ultrarapid diagnostic methods are introduced as routine tools in clinical practice or the pricing of such special drugs reflects the costs of their development.

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