Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

Most bacteria use an indirect pathway to generate aminoacylated glutamine and/or asparagine tRNAs. Clinical isolates of with increased rates of error in gene translation (mistranslation) involving the indirect tRNA-aminoacylation pathway have increased tolerance to the first-line antibiotic rifampic...

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Bibliographic Details
Published in:	eLife Vol. 7
Main Authors:	Chaudhuri, Swarnava, Li, Liping, Zimmerman, Matthew, Chen, Yuemeng, Chen, Yu-Xiang, Toosky, Melody N, Gardner, Michelle, Pan, Miaomiao, Li, Yang-Yang, Kawaji, Qingwen, Zhu, Jun-Hao, Su, Hong-Wei, Martinot, Amanda J, Rubin, Eric J, Dartois, Veronique Anne, Javid, Babak
Format:	Journal Article
Language:	English
Published:	England eLife Science Publications, Ltd 28-08-2018 eLife Sciences Publications Ltd eLife Sciences Publications, Ltd
Subjects:	Aminoacylation Aminoglycoside antibiotics Aminoglycosides - administration & dosage Aminoglycosides - pharmacokinetics Aminoglycosides - pharmacology Aminoglycosides - therapeutic use Analysis Animal experimentation Animal models Animals Antibacterial agents antibiotic tolerance Antibiotics Asparagine Bacteria Clinical isolates Communicable diseases Drug Resistance, Bacterial - drug effects Drug Synergism E coli Edeine - pharmacology Experiments Genes Genetic code Glutamine Health aspects Infections Infectious diseases Injections, Intraperitoneal Kasugamycin Lungs Medical research Mice Microbial drug resistance Microbial Sensitivity Tests Microbiology and Infectious Disease Minimum inhibitory concentration mistranslation Mutation Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects Novels Organ Specificity persister Protein Biosynthesis - drug effects Proteins Public health Rifampin Rifampin - pharmacology Rifampin - therapeutic use RNA RNA, Transfer - metabolism Scientists Statistical analysis Streptomycin Streptomycin - administration & dosage Streptomycin - pharmacokinetics Streptomycin - pharmacology Streptomycin - therapeutic use Students Transfer RNA Translation (Genetics) tRNA Tuberculosis Tuberculosis - drug therapy Tuberculosis - microbiology Tuberculosis - pathology United States > US New Jersey mouse Mycobacterium tuberculosis infectious disease antibiotic tolerance kasugamycin microbiology mistranslation persister
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Summary:	Most bacteria use an indirect pathway to generate aminoacylated glutamine and/or asparagine tRNAs. Clinical isolates of with increased rates of error in gene translation (mistranslation) involving the indirect tRNA-aminoacylation pathway have increased tolerance to the first-line antibiotic rifampicin. Here, we identify that the aminoglycoside kasugamycin can specifically decrease mistranslation due to the indirect tRNA pathway. Kasugamycin but not the aminoglycoside streptomycin, can limit emergence of rifampicin resistance in vitro and increases mycobacterial susceptibility to rifampicin both in vitro and in a murine model of infection. Moreover, despite parenteral administration of kasugamycin being unable to achieve the in vitro minimum inhibitory concentration, kasugamycin alone was able to significantly restrict growth of in mice. These data suggest that pharmacologically reducing mistranslation may be a novel mechanism for targeting bacterial adaptation.
Bibliography:	These authors contributed equally to this work.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.36782