M. tuberculosis Hypothetical Proteins and Proteins of Unknown Function: Hope for Exploring Novel Resistance Mechanisms as well as Future Target of Drug Resistance

Abstract

Drug resistance in tuberculosis predominantly, mono-resistance, multi drug resistance, extensively drug resistance and totally drug resistance have emerged as a major problem in the chemotherapy of tuberculosis. Failures of first and second line anti-tuberculosis drugs treatment leads to emergence of resistant Mycobacterium tuberculosis. Few genes are reported as the principal targets of the resistance and apart from the primary targets many explanations have been proposed for drug resistance but still some resistance mechanisms are unknown. As proteins involved in most of the biological processes, these are potentially explored the unknown mechanism of drug resistance and attractive targets for diagnostics/future therapeutics against drug resistance. In last decade a panel of studies on expression proteomics of drug resistant M. tuberculosis isolates reported the differential expression of uncharacterized proteins and suggested these might be involved in resistance. Here we emphasize that detailed bioinformatics analysis (like molecular docking, pupylation, and proteins-proteins interaction) of these uncharacterized and hypothetical proteins might predict their interactive partners (other proteins) which are involved in various pathways of M. tuberculosis system biology and might give a clue for novel mechanism of drug resistance or future drug targets. In future these uncharacterized targets might be open the new resistance mechanism and used as potential drug targets against drug resistant tuberculosis.

Detecting Ethambutol Resistance in Mycobacterium tuberculosis Isolates in China: A Comparison Between Phenotypic Drug Susceptibility Testing Methods and DNA Sequencing of embAB

“…There were still some EMB-resistant isolates determined by phenotypic DST methods (PM, MGIT, and MABA), which lacked embAB mutations. This implied that these strains probably harbored mutations outside embAB (Safi et al, 2013;He et al, 2015;Tulyaprawat et al, 2019) or that the resistance may have been caused by other mechanisms, such as overexpressed efflux pumps and loss of porins (Sharma and Bisht, 2017;Sharma et al, 2018). Careful interpretation of a negative DNA sequencing result (no mutation) is thus necessary in the accurate management of suspected DR-TB.…”

“…However, the presence of these mutations in embAB was also observed in EMBsusceptible isolates (Shi et al, 2011;Zhao et al, 2015;Li et al, 2016;Sun et al, 2018). Besides, there are no mutations within the particular genes responsible for EMB resistance in some EMB-resistant isolates, implying the involvement of other resistance mechanisms (Sharma and Bisht, 2017;Sharma et al, 2018). As per the literature, significant discordance exists between the phenotypic and genotypic methods for EMB susceptibility testing (Kim, 2005;Garrigo et al, 2007;Cheng et al, 2014;Zhang et al, 2014).…”

Potential Alternative Strategy against Drug Resistant Tuberculosis: A Proteomics Prospect

“…Expression proteomics {2-dimensional gel electrophoresis (2-DE)} coupled with MALDI-TOF-MS and bioinformatic tools has emerged as a direct approach for the separation, identification and characterization of proteins which could be used to find out potential drug targets and diagnosis of resistance as well as pathogenesis [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Since the last decade, a panel of discovery (expression), targeted proteomics and bioinformatics-based studies [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] have been accumulated on M. tuberculosis pathogenesis and drug resistance which showed differential expression of a panel of known and unknown proteins and suggested that these proteins might be used in diagnostics and as drug targets against drug resistant TB. We have previously reported that Rv0148 (hypothetical protein/putative short-chain type dehydrogenase/reductase) was overexpressed in aminoglycosides-resistant M. tuberculosis .…”

Clinical Proteomics and Bioinformatics: Exploring Drug Resistant Tuberculosis

“…Differential expressions of known and hypothetical proteins (functionally unknown) have reported in drug-resistant strains of M. tuberculosis. In-silico analysis (Molecular Docking, KEGG Pathways, Pupylome, and Interactome) of these proteomes explored the possible pathways as well as subsequent targets involved in the drug resistance [16][17][18][19][20][21]. Selected proteins and subsequent targets of the affiliated pathways might serve as the possible diagnostics and therapeutic targets for the development of alternative strategies against the drug resistance.…”