Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics.

Tomislav Jednačak,Predrag Novak,Ivana Mikulandra

doi:10.3390/ijms21207799

Tomislav Jednačak, Predrag Novak + Show 1 more

Open Access

https://doi.org/10.3390/ijms21207799

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Abstract

Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, their excellent antibacterial profile was largely compromised by the emergence of bacterial resistance. Today, fighting resistance to antibiotics is one of the greatest challenges in medicinal chemistry. Considering various physicochemical properties of macrolides, understanding their structure and interactions with macromolecular targets is crucial for the design of new antibiotics efficient against resistant pathogens. The solid-state structures of some macrolide-ribosome complexes have recently been solved, throwing new light on the macrolide binding mechanisms. On the other hand, a combination of NMR spectroscopy and molecular modeling calculations can be applied to study free and bound conformations in solution. In this article, a description of advanced physicochemical methods for elucidating the structure and interactions of macrolide antibiotics in solid state and solution will be provided, and their principal advantages and drawbacks will be discussed.

Highlights

Owing to their high efficacy and safety, macrolide antibiotics have been in widespread clinical use for over 50 years
The results indicated that macrolide binding to lipids protected them from being degraded by phospholipase A1
The advanced experimental and computational methods reviewed in this paper have successfully been applied to study the structure and interactions of macrolide antibiotics with their biological targets

Summary

Introduction

Owing to their high efficacy and safety, macrolide antibiotics have been in widespread clinical use for over 50 years. Structures of some macrolide-ribosome complexes have recently been solved by X-ray crystallography and cryogenic electron microscopy (cryo-EM), throwing new light on the binding mechanisms of macrolides to the ribosome and providing a good basis for the design of new ligands and inhibitors [10,11,12,13,14,15] This is a very important research field to the worldwide scientific community since the Nobel Prize for 2009 in Chemistry was awarded to groups studying the ribosome and its complexes with antibiotics. Since macrolide antibiotics may have different physicochemical properties and bioactivity, a detailed description of their structure and interactions with macromolecular receptors is crucial for assessing the overall biological profile It can provide an insight into the macrolide binding mechanisms and facilitate the elucidation of biological effects exerted by this class of antibiotics on the human body. Recent applications of the advanced experimental and computational tools for studying the structure and interactions of macrolide antibiotics are described, and their main advantages and drawbacks are discussed

X-ray Structure Characterization of Macrolide-Ribosome Complexes

Cryo-EM Imaging of Macrolide-Targeted Ribosomes

Probing Macrolide Interactions by NMR Spectroscopy

Other Methods for Macrolide Binding Studies

Computational Simulations of Macrolide Interactions

Conclusions