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Toward the rational design of macrolide antibiotics to combat resistance
Anna Pavlova1, Jerry M Parks2, Adegboyega K Oyelere3
1School of Physics, Georgia Institute of Technology, Atlanta, GA, USA.
Abstract:
Macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated Escherichia coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from their crystal structure position, illuminating the causes of resistance. We have also examined four azithromycin derivatives containing aromatic indole-analog moieties, which were previously designed based on simulations of the stalling peptide SecM in the ribosome. Surprisingly, we found that the studied moieties could adopt very different geometries when interacting with a key base in the tunnel, A751, possibly explaining their distinct activities. Based on our simulations, we propose modifications to the indole-analog moieties that should increase their interactions with A751 and, consequently, enhance the potency of future azithromycin derivatives.
Insights
Antibiotic resistance is growing due to mutations in bacterial ribosomes. Molecular dynamics simulations reveal how these changes, particularly at base A2058, reduce macrolide antibiotic effectiveness, guiding the development of new drugs.
Area of Science:
- Molecular Biology
- Biochemistry
- Computational Chemistry
Background:
- Macrolide antibiotics are crucial for inhibiting bacterial translation by binding to the ribosome's polypeptide exit tunnel.
- Emerging resistance to macrolides, often due to mutations at base A2058 of 23S rRNA, poses a significant public health threat.
- Understanding the molecular mechanisms of resistance is vital for developing effective antibiotics.
Purpose of the Study:
- To investigate the impact of specific ribosomal modifications (A2058G mutation, A2058 methylation) on macrolide binding and function using molecular dynamics simulations.
- To explore the binding interactions of novel azithromycin derivatives with the bacterial ribosome, particularly focusing on interactions with A751.
- To propose structural modifications for azithromycin derivatives to enhance their potency against resistant bacteria.
Main Methods:
- Utilized molecular dynamics (MD) simulations to model erythromycin and azithromycin interactions with wild-type and modified Escherichia coli ribosomes.
- Analyzed changes in macrolide-ribosome interactions, including base-sugar interactions and positional displacement, in response to A2058 modifications.
- Simulated the binding of four azithromycin derivatives with indole-analog moieties to the ribosome, focusing on their interactions with ribosomal base A751.
Main Results:
- Ribosomal modifications at A2058 significantly weakened interactions with macrolides and increased their displacement from the binding site, explaining resistance mechanisms.
- Azithromycin derivatives exhibited varied binding geometries with A751, correlating with their observed biological activities.
- The study identified specific structural features of azithromycin derivatives that influence their interaction with key ribosomal bases.
Conclusions:
- Ribosomal base modifications at A2058 are a key driver of macrolide antibiotic resistance by disrupting drug binding.
- The binding modes of azithromycin derivatives are conformation-dependent and influence their efficacy.
- Proposed structural modifications to azithromycin derivatives targeting interactions with A751 could lead to more potent antibiotics against resistant strains.