Mycobacterium tuberculosis Rv1152 is a Novel GntR Family Transcriptional Regulator Involved in Intrinsic Vancomycin Resistance and is a Potential Vancomycin Adjuvant Target.

Jie Zeng,Rui Wang,Wanyan Deng,Abualgasim Elgaili Abdalla,Hongping Luo,Tiwei Fu,Jianping Xie,Ping Li,Xiangke Duan,Longxiang Xie,Wenmin Yang

doi:10.1038/srep28002

Abstract

Novel factors involved in Mycobacteria antibiotics resistance are crucial for better targets to combat the ever-increasing drug resistant strains. Mycobacterium tuberculosis Rv1152, a novel GntR family transcriptional regulator and a promising vancomycin adjuvant target, was firstly characterized in our study. Overexpression of Rv1152 in Mycobacterium smegmatis decreased bacterial susceptibility to vancomycin. Moreover, a deficiency in MSMEG_5174, an Rv1152 homolog made M. smegmatis more sensitive to vancomycin, which was reverted by complementing the MSMEG_5174 deficiency with Rv1152 of M. tuberculosis. Rv1152 negatively regulated four vancomycin responsive genes, namely genes encoding the ribosome binding protein Hsp, small unit of sulfate adenylyltransferase CysD, L-lysine-epsilon aminotransferase Lat, and protease HtpX. Taken together, Rv1152 controls the expression of genes required for the susceptibility to vancomycin. This is the first report that links the GntR family transcriptional factor with vancomycin susceptibility. Inhibitors of Rv1152 might be ideal vancomycin adjuvants for controlling multi-drug resistant Mycobacterial infections.

Highlights

A replicative plasmid expressing two phage recombinases and conferring kanamycin (Km) resistance the effector binding[11], namely FadR, HutC, MocR, YtrA, AraR and PlmA13,14
These results suggest that the overexpression of Rv1152 in M. smegmatis modified the M. smegmatis response to surface and acid stress
Its prolonged chronic infection requires the expression of a complex array of genetic determinants, including those involved in secondary metabolism, cell wall processes, stress responses, and signal transduction[40]

Summary

Introduction

A replicative plasmid expressing two phage recombinases and conferring kanamycin (Km) resistance the effector binding[11], namely FadR, HutC, MocR, YtrA, AraR and PlmA13,14. We identified a novel M. tuberculosis GntR family regulator, Rv1152, which can alter cell wall permeability of M. smegmatis to acid and surface stress and play an important in vancomycin loss of susceptibility through negatively regulating the genes responsive to vancomycin. M. smegmatis overexpressed M. tuberculosis Rv1152 (MS_Rv1152) was more resistant to vancomycin than M. smegmatis harboring the vector only (MS_Vec), while the MSMEG_5174 (the homologous gene of Rv1152 in M. smegmatis) deletion mutant (△MSMEG_5174) was more sensitive to vancomycin than the wild type M. smegmatis. The genes regulated by Rv1152 are responsible for the sensitivity of M. smegmatis to vancomycin These data suggest that Rv1152 involved in the loss of susceptibility to vancomycin through negatively regulating the expression of vancomycin responsive genes

Methods

Results

Conclusion