measurement-specific-mycobacterial-mistranslation-rates-with-gain

Measurement of Specific Mycobacterial Mistranslation Rates with Gain-of-function Reporter Systems

The translation of genes into proteins is prone to errors. Although the average rate of translational error in model systems is estimated to be 1/10,000 ...

Tsinghua University School of Medicine

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.

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

Metrics commonly used to describe antibiotic efficacy rely on measurements performed on bacterial populations. However, certain cells in a bacterial population can continue to grow and divide, even at antibiotic concentrations that kill the majority of cells, in a phenomenon known as antibiotic tolerance. Here, we describe a form of semi-heritable tolerance to the key anti-mycobacterial agent rifampicin, which is known to inhibit transcription by targeting the β subunit of the RNA polymerase (RpoB). We show that rifampicin exposure results in rpoB upregulation in a sub-population of cells, followed by growth. More specifically, rifampicin preferentially inhibits one of the two rpoB promoters (promoter I), allowing increased rpoB expression from a second promoter (promoter II), and thus triggering growth. Disruption of promoter architecture leads to differences in rifampicin susceptibility of the population, confirming the contribution of rifampicin-induced rpoB expression to tolerance.

Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription.

It has been shown that intracranial artery stenosis (ICAS) plays a key role in Chinese ischemic stroke or transient ischemic attack (TIA) patients. Many vascular diseases can lead to ICAS, such as atherosclerosis, dissection, vasculitis, moyamoya disease, and reversible cerebral vasoconstriction syndrome (RCVS). In addition, progression of intracranial atherosclerotic disease (ICAD) will increase the risk of ischemic cerebrovascular events. The ICASMAP study primarily aims to determine the etiology and disease distribution of ICAS using noninvasive magnetic resonance (MR) imaging and evaluate the rate for progression of ICAD in symptomatic population.

Miamiao Pan

Centre for Global Health and Infectious Diseases,
Collaborative Innovation Centre for the Diagnosis and Treatment of Infectious Diseases,
Centre for Global Health and Infectious Diseases, Collaborative Innovation Centre for the Diagnosis and Treatment of Infectious Diseases

Tsinghua University School of Medicine

Measurement of Specific Mycobacterial Mistranslation Rates with Gain-of-function Reporter Systems