Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance

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.
Antibiotic resistance is a major threat to global health; this problem can be addressed by the development of new antibacterial agents to keep pace with the evolutionary adaptation of pathogens. Computational approaches are essential tools to this end since their application enables fast and early strategical decisions in the drug development process. We present a rational design approach, in which acylide antibiotics were screened based on computational predictions of solubility, membrane permeability, and binding affinity toward the ribosome. To assess our design strategy, we tested all candidates for in vitro inhibitory activity and then evaluated them in vivo with several antibiotic-resistant strains to determine minimal inhibitory concentrations. The predicted best candidate is synthetically more accessible, exhibits higher solubility and binding affinity to the ribosome, and is up to 56 times more active against resistant pathogens than telithromycin. Notably, the best compounds designed by us show activity, especially when combined with the membrane-weakening drug colistin, against Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli, which are the three most critical targets from the priority list of pathogens of the World Health Organization.