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Chapter 10. Restricting Antibiotic Use a... > Consideration of Resistance During D...

Consideration of Resistance During Drug Discovery

Finding new antibiotic classes is difficult. Consequently, most of the work over the last 30 years has been devoted to refining existing classes to make the compounds slightly more potent with a broader pathogen spectrum. As we move forward one step at a time, the pathogens also move forward, one mutation at a time. Moving one mutational step is easy for the pathogens, because their populations can be so large that cells with one resistance mutation are abundant. Consequently, our efforts have only been holding pathogens at bay; new antibiotics are neither expected nor designed to restrict the emergence of resistance.

As pointed out previously, conventional antibiotic discovery efforts focus on finding compounds with low MIC and low mammalian toxicity. No antibiotic has been developed with restriction of resistance as a criterion. When resistance has been recognized as an important factor in therapy, multiple antibiotics having different molecular targets have been used to address the problem. (Examples are the current multidrug regimens for tuberculosis and HIV disease.) In some cases, it has also been possible to find specific inhibitors of resistance proteins. (ß-lactamase inhibitors enable ß-lactams to be effective.) The selection window hypothesis now leads to an approach for finding compounds that will themselves restrict the emergence of resistan....Box 10-7


  

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