National Academy of Sciences, Proceedings of the National Academy of Sciences, 46(118), 2021
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Significance Due to the development of resistance against commonly used antibiotics, new derivatives that avoid resistance mechanisms need to be developed. To address this problem, a rational prioritization strategy is outlined for macrolide antibiotics. Candidates are screened based on their solubility, membrane permeability, and binding affinity using a tiered optimization approach of free energy simulations and quantum mechanics/molecular mechanics calculations. After prioritization by computational methods, the best candidates are evaluated experimentally. The strategy creates a targeted substance library that is highly enriched in compounds with antibacterial activity. This allows for faster iterations in the development of new antibiotic derivatives.