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Multi-target potency. Lethal bioavailability. Metabolic decoys


Antibiotics, the panacea for bacterial infections, are becoming increasingly ineffective as bacteria develop resistance mechanisms to every class of antibacterial drugs. Pitted against the adaptive power of rapid and strong selection for resistant bacterial strains, we are losing ground in an arms race that the World Health Organization warns...





A POST-ANTIBIOTIC ERA

Antibiotics, the panacea for bacterial infections, are becoming increasingly ineffective as bacteria develop resistance mechanisms to every class of antibacterial drugs. Pitted against the adaptive power of rapid and strong selection for resistant bacterial strains, we are losing ground in an arms race that the World Health Organization warns could end in a post-antibiotic era “in which common infections and minor injuries can kill.”

New antibiotics with novel mechanisms of action are imperative to revitalize the antibiotic arsenal, but they have not yet materialized. Since the climax in antibiotic discovery during the 1940s and 50s, a dwindling number of truly new antibacterial compounds have been approved for clinical use. Amassing knowledge about the behavior of compounds in the body and new technologies to predict their interactions with targets guide the design of new compounds, but in the end, nothing substitutes the painstaking process of testing and re-testing promising analogs. Optimization of the antibacterial or physical properties of a drug often comes at the expense of other important attributes, so that achieving the right balance for therapeutic efficacy – finding the sweet spot of a killer – is frequently educated trial and error.
"New antibiotics with novel mechanisms of action are imperative to revitalize the antibiotic arsenal, but they have not yet materialized"


" And how do you maximize broad-spectrum antibacterial potency without compromising the first two traits?"
Five programs aimed at the discovery and optimization of antibacterial compounds targeting the enzymes DNA gyrase and topoisomerase IV highlight some of the challenges to develop novel antibiotics that meet often-conflicting criteria. Gyrase and topoisomerase IV are ideal targets. Structurally similar and essential for bacterial survival, a single compound can bind and inhibit both enzymes concurrently, presenting the opportunity for dual-targeting activity to raise the barrier against resistance development. But how do you achieve the necessary solubility? How do you avoid impairing binding with serum proteins? And how do you maximize broad-spectrum antibacterial potency without compromising the first two traits? Answering these types of questions is key to successfully develop the needed antibiotics and, as the programs examined in this article repeatedly demonstrate, with time and creativity the answers can be found....