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Understanding Mechanistic Details of Ribosomal Methyltransferases Involved in Antibiotic Resistance
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(S 01): S1-S16
DOI: DOI: 10.1055/s-0044-1788222
*Corresponding author: (e-mail: daminisahu20@gmail.com; ruchi.chem@iitb.ac.in).
Abstract
Introduction: Antibiotic resistance in pathogens is a threat and it is imperative to develop drugs curbing resistance. Selective methylation of nucleobases in ribosome is common to gaining resistance. Erythromycin-resistant methyltransferases catalyze the methylation of A2058 of ribosomal RNA and prevent binding of macrolides by creating steric clash at their binding pocket.
Materials and Methods: Our research is dedicated to developing inhibitors for the Erm family of enzymes, with the goal of reversing antibiotic resistance. Small molecules were selected using virtual screening. Colorimetric methylation assay was used for high throughput screening of these molecules. Select molecules were further assayed using scintillation assay.
Results: Small molecules were virtually screened focusing on crucial regions in the Erm to develop specific inhibitors. Several small-molecule libraries were virtually screened and the top hits were experimentally validated. The resulting hits were further assessed using a scintillation-based assay leading to identification of few molecules that proved to be potent inhibitors. Notably, two of these molecules demonstrated promising efficacy both in vitro and in vivo.
Conclusion: These discoveries hold great potential for combating antibiotic resistance and it would be interesting to study the interactions between the protein and the potential inhibitors. The potential small-molecule inhibitors will be crystallized further in presence of protein.
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
*Corresponding author: (e-mail: daminisahu20@gmail.com; ruchi.chem@iitb.ac.in).
Abstract
Introduction: Antibiotic resistance in pathogens is a threat and it is imperative to develop drugs curbing resistance. Selective methylation of nucleobases in ribosome is common to gaining resistance. Erythromycin-resistant methyltransferases catalyze the methylation of A2058 of ribosomal RNA and prevent binding of macrolides by creating steric clash at their binding pocket.
Materials and Methods: Our research is dedicated to developing inhibitors for the Erm family of enzymes, with the goal of reversing antibiotic resistance. Small molecules were selected using virtual screening. Colorimetric methylation assay was used for high throughput screening of these molecules. Select molecules were further assayed using scintillation assay.
Results: Small molecules were virtually screened focusing on crucial regions in the Erm to develop specific inhibitors. Several small-molecule libraries were virtually screened and the top hits were experimentally validated. The resulting hits were further assessed using a scintillation-based assay leading to identification of few molecules that proved to be potent inhibitors. Notably, two of these molecules demonstrated promising efficacy both in vitro and in vivo.
Conclusion: These discoveries hold great potential for combating antibiotic resistance and it would be interesting to study the interactions between the protein and the potential inhibitors. The potential small-molecule inhibitors will be crystallized further in presence of protein.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India