Proteomic analysis of ofloxacin-mono resistant Mycobacterium tuberculosis isolates.
J Proteomics. 2015 Jul 31;
Authors: Lata M, Sharma D, Deo N, Tiwari PK, Bisht D, Venkatesan K
Drug resistance particularly, multi drug resistance tuberculosis (MDR-TB) has emerged as a major problem in the chemotherapy of tuberculosis. Ofloxacin (OFX) has been used as second-line drug against MDR-TB. The principal target of the OFX is DNA gyrase encoded by gyrA and gyrB genes. Many explanations have been proposed for drug resistance to OFX but still some mechanisms are unknown. As proteins manifest most of the biological processes, these are attractive targets for developing drugs and diagnostics/therapeutics. We examined the OFX resistant M.tuberculosis isolates by proteomic approach (2DE-MALDI-TOF-MS) and bioinformatic tools under OFX induced conditions. Our study showed fourteen proteins (Rv0685, Rv0363c, Rv2744c, Rv3803c, Rv2534c, Rv2140c, Rv1475c, Rv0440, Rv2245, Rv1436, Rv3551, Rv0148, Rv2882c and Rv0733) with increased intensities in OFX resistant and OFX induced as compared to susceptible isolates. Bioinformatic analysis of hypothetical proteins (Rv2744c, Rv2140c, Rv3551 and Rv0148) revealed the presence of conserved motifs and domains. Molecular docking showed proper interaction of OFX with residues of conserved motifs. These proteins might be involved in the OFX modulation/neutralization and act as novel resistance mechanisms as well as potential for diagnostics and drug targets against OFX resistance.
BIOLOGICAL SIGNIFICANCE: In this study we employed two dimensional gel electrophoresis coupled with mass spectrometry and bioinformatics tools. To the best of our knowledge it is the first ever report on proteomics of ofloxacin (OFX) resistant M. tuberculosis isolates and their induction with OFX. Out of fourteen proteins (increased intensities) four proteins (Rv2744c, Rv2140c, Rv3551 and Rv0148) were with unknown functions. Molecular docking revealed that conserved motifs of hypothetical proteins interact with OFX. We hypothesized that these proteins might be neutralizing the effect of OFX, explored novel resistance mechanism and in survival of mycobacteria in the presence of OFX. These findings need further exploitation to develop newer therapeutic agents against these targets.
PMID: 26238929 [PubMed - as supplied by publisher]