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

Gerhard König, Pandian Sokkar, Niclas Pryk, Sascha Heinrich, David Möller, Giuseppe Cimicata, Donna Matzov, Pascal Dietze, Walter Thiel, Anat Bashan, Julia Elisabeth Bandow, Johannes Zuegg, Ada Yonath, Frank Schulz, Elsa Sanchez-Garcia

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Abstract

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.
Original languageEnglish
Article numbere2113632118
Number of pages7
JournalProceedings of the National Academy of Sciences
Volume118
Issue number46
Early online date8 Nov 2021
DOIs
Publication statusPublished - 16 Nov 2021

Keywords

  • ribosome
  • QM/MM
  • antibiotics
  • resistance
  • free energy

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