Why is it so difficult to discover and develop new antibiotics?
Eisenstein: It is inherently more difficult today to identify and develop new antibiotics than it was 30 to 50 years ago when most of the better-known, orally bioavailable, and broad-spectrum antibiotics were discovered. Bacterial targets, by their nature, are not easy; they must be essential, conserved across bacterial species and unique to bacteria. However, many of the original antibiotics were potent, nontoxic small molecules that were derived from natural products and could be easily modified by traditional medicinal chemistry — to improve their potency and safety and overcome emerging resistance mechanisms. This gave rise to various generations of certain antibiotics including the cephalosporins, macrolides, and aminoglycosides. Each generation had incremental improvements over the last, but the mode of action remained the same. Companies in the antibiotic discovery space relied on this model to develop new products until the mid-1990s when it became evident that new antibiotics
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