NDLI: Tools for Characterizing Bacterial Protein Synthesis Inhibitors

Content Provider	PubMed Central
Author	Orelle, Cédric Carlson, Skylar Kaushal, Bindiya Almutairi, Mashal M. Liu, Haipeng Anna, Ochabowicz Quan, Selwyn Pham, Van Cuong Squires, Catherine L. Murphy, Brian T. Mankin, Alexander S.
Copyright Year	2013
Abstract	Many antibiotics inhibit the growth of sensitive bacteria by interfering with ribosome function. However, discovery of new protein synthesis inhibitors is curbed by the lack of facile techniques capable of readily identifying antibiotic target sites and modes of action. Furthermore, the frequent rediscovery of known antibiotic scaffolds, especially in natural product extracts, is time-consuming and expensive and diverts resources that could be used toward the isolation of novel lead molecules. In order to avoid these pitfalls and improve the process of dereplication of chemically complex extracts, we designed a two-pronged approach for the characterization of inhibitors of protein synthesis (ChIPS) that is suitable for the rapid identification of the site and mode of action on the bacterial ribosome. First, we engineered antibiotic-hypersensitive Escherichia coli strains that contain only one rRNA operon. These strains are used for the rapid isolation of resistance mutants in which rRNA mutations identify the site of the antibiotic action. Second, we show that patterns of drug-induced ribosome stalling on mRNA, monitored by primer extension, can be used to elucidate the mode of antibiotic action. These analyses can be performed within a few days and provide a rapid and efficient approach for identifying the site and mode of action of translation inhibitors targeting the bacterial ribosome. Both techniques were validated using a bacterial strain whose culture extract, composed of unknown metabolites, exhibited protein synthesis inhibitory activity; we were able to rapidly detect the presence of the antibiotic chloramphenicol.
Related Links	http://dx.doi.org/10.1128/aac.01673-13
Ending Page	6004
Page Count	11
Starting Page	5994
File Format	PDF
ISSN	00664804
e-ISSN	10986596
Journal	Antimicrobial Agents and Chemotherapy
Issue Number	12
Volume Number	57
Language	English
Publisher	American Society for Microbiology
Publisher Date	2013-12-01
Access Restriction	Open
Rights Holder	American Society for Microbiology
Subject Keyword	Pharmacology (medical) Pharmacology Infectious Diseases Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Pharmacology Pharmacology (medical)

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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