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Papers by Nusrath Unissa

Despite the availability of various techniques for diagnosis; the presence of improved and modifi... more Despite the availability of various techniques for diagnosis; the presence of improved and modified version of vaccines and the existence of more than a dozen of drugs, tuberculosis still remains as a significant infectious disease. The publication of complete genome of Mycobacterium tuberculosis has lead to the development of new genetic tools to ascertain the functioning of individual genes, leading to subsequent identification and validation of potential drug targets. With the help of Rational Drug designing, a computer-aided approach to find molecules with desired chemical and geometric properties that bind in a receptor cavity of specific target protein. It is hoped that promising new drugs for the effective treatment of not only TB also for MDR, XDR, HIV and persistent TB will be possible in the near future.

Altered drug binding may be an important factor in isoniazid (INH) resistance, rather than major ... more Altered drug binding may be an important factor in isoniazid (INH) resistance, rather than major changes in the enzyme's activity as a catalase or peroxidase (KatG). The identification of structural or functional defects in the mutant KatGs responsible for INH resistance remains as an area to be explored. In this connection, the differences in the binding affinity between wild-type (WT) and mutants of KatG were investigated, through the generation of three mutants of KatG, Ser315Thr [S315T], Ser315Asn [S315N], Ser315Arg [S315R] and a WT [S315]) with the help of software-MODELLER. The mutants were docked with INH using the software-GOLD. The affinity is lower for WT than mutant, suggesting the tight binding of INH with the mutant protein compared to WT type. These models provide the <em>in silico</em> evidence for the binding interaction of KatG with INH and implicate the basis for rationalization of INH resistance in naturally occurring KatG mutant strains of <em&...

Insight to pyrazinamide resistance in Mycobacterium tuberculosis by molecular docking

Mycobacterium tuberculosis

Copyright © 2015 A. Nusrath Unissa et al. This is an open access article distributed under the Cr... more Copyright © 2015 A. Nusrath Unissa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mutation at codon 315 of katG gene is themajor cause for isoniazid (INH) resistance inMycobacterium tuberculosis (M. tuberculosis). Substitution at codon 315 of katG gene was analyzed in 85 phenotypically resistant isolates collected from various parts of southern India by direct sequencing method. The obtained results were interpreted in the context of minimum inhibitory concentration (MIC) of INH. Of the 85 phenotypically resistant isolates, 56 (66%) were also correlated by the presence of resistance mutations in the katG gene; 47 of these isolates had ACC, 6 had AAC, 2 had ATC, and one had CGC codon.The frequency of Ser315 substitution in katG gene was found to be higher (70%) amongstmultidrug-resistant (MDR) strains than among...

Big Data Analytics in HIV/AIDS Research, 2018

Protease (PR) is an important enzyme required for the posttranslational processing of the viral g... more Protease (PR) is an important enzyme required for the posttranslational processing of the viral gene products of type-1 human immunodeficiency virus (HIV-1). Protease inhibitors (PI) act as competitive inhibitors that bind to the active site of PR. The I84V mutation contributes resistance to multiple PIs, and structurally, this mutation affects both sides of the enzyme active site. In order to get insights about this major resistance site to PR inhibitors using in silico approaches, in this chapter, the wild-type (WT) and mutant (MT) I84V of PR were modeled and docked with all PR inhibitors: Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Saquinavir, and Tipranavir. Docking results revealed that in comparison to the WT, the binding score was higher for the MT-I84V. Thus, it can be suggested that the high affinity towards inhibitors in the MT could be due to the presence of energetically favorable interactions, which may lead to tight binding of inhibitors with the MT protei...

International journal of pharma and bio sciences, 2012

Bedaquiline (BDQ) is the new first-in-class anti-tuberculosis (TB) compound belonging to the clas... more Bedaquiline (BDQ) is the new first-in-class anti-tuberculosis (TB) compound belonging to the class of diarylquinolone with activity against drug-sensitive and drug-resistant Mycobacterium tuberculosis (M. tuberculosis). This novel drug has the immense potential to shorten TB treatment duration and has been advocated for multi-drug resistant (MDR)-TB treatment. Therefore, BDQ resistance can be considered as a major public health problem and molecular investigation of the same is the utmost need of the hour. The target based concept of resistance to BDQ is caused by mutation in c-ring of adenosine tri phosphate (ATP) synthase, a critical enzyme in the synthesis of ATP in M. tuberculosis coded by atpE gene. BDQ inhibits the proton pump of mycobacterial ATP synthase. To understand the molecular basis of BDQ resistance using mutants (MTs) as the emergence of strains resistant to BDQ may pose a potential threat to the TB control program, we undertook a initiative to study seven in vitro m...

Big Data Analytics in HIV/AIDS Research

Reverse transcriptase (RT) is a vital enzyme in the process of transcription of HIV-1. The nucleo... more Reverse transcriptase (RT) is a vital enzyme in the process of transcription of HIV-1. The nucleoside analogues of RT inhibitors (NRTIs) act by substrate competition and chain termination as they resemble a nucleotide. To understand the basis of RT resistance in HIV-1, in this chapter, one of the clinically essential mutants Q151M of RT which exhibits multi-resistance to many NRTIs was modeled and docked with NRTIs in comparison to wild type (WT). The results of docking indicate that the WT showed high affinity with all inhibitors compared to the mutant (MT). It can be suggested that the high affinity in WT could be attributed to the favorable interactions with all inhibitors that lacks in MT due to amino acid substitution that leads to structural changes in MT protein, which alters the favorable network of interaction and eventually imparts resistance to all inhibitors.

Journal of global antimicrobial resistance, Jan 7, 2018

Isoniazid (INH) is still the most important first-line anti-tuberculosis (TB) drug. Resistance to... more Isoniazid (INH) is still the most important first-line anti-tuberculosis (TB) drug. Resistance to this drug is regarded as a major impediment on the TB control program and to the emergence of multidrug-resistant strains. Mutations at position 315 in the katG gene which codes for catalase-peroxidase (KatG) enzyme, is the major cause for INH resistance in Mycobacterium tuberculosis (MTB). Therefore, investigation into the molecular mechanisms of INH resistance is the need of the hour. To understand the clinical importance of five mutants (MTs) of KatG which lead to INH resistance, in this study, 5 MTs -S315T; S315I; S315R; S315N and S315G were modeled, docked and interacted with INH in dynamic state. The binding affinity based on docking was found to be higher for MTs than the wild-type (WT) except for MT-S315R, indicating a rigid binding of INH with MT proteins as compared to the flexible binding seen in the WT. Analysis of molecular dynamics (MD) experiments suggest that fluctuation...

Tuberculosis and Respiratory Diseases, 2017

form by an enzyme catalase and peroxidase (CP) or KatG. The loss of CP or KatG activities in MTB ... more form by an enzyme catalase and peroxidase (CP) or KatG. The loss of CP or KatG activities in MTB has long been correlated with resistance to INH 2,3. Multiple genes (katG, inhA, and others) with specific mutations have been associated with INH resistance 4-6. Of these, mutations in katG are responsible for high level resistance and inhA promoter mutations lead to low-level INH resistance. Of all other genes excluding

International Journal of Pharma and Bio Sciences, 2017

Journal of global antimicrobial resistance, Jan 22, 2017

In order to identify good leads based on isoniazid (INH) derivatives against INH resistance, whic... more In order to identify good leads based on isoniazid (INH) derivatives against INH resistance, which is one of the major contributors to the emergence of multidrug-resistant (MDR) that hampers the success of tuberculosis treatment. Mutations at codon 315 in the katG gene coding for catalase-peroxidase (KatG) is the major cause for INH resistance in Mycobacterium tuberculosis(MTB). The most prevalent mutation at this codon is Ser to Thr substitution (S315T). The other substitutions include S315I, S315R, S315N and S315G. In this study, all the 5 (S315T, S315I, S315R, S315N and S315G) mutants (MTs) were docked and simulated with 50 derivatives of INH in comparison to the wild type (WT-S315). The docking results suggest that compounds (C)-30, 45 and 50, gave the highest scores when bound to the MTs of KatG. Of note, the C-50 produced high score with the WT as well three MTs (S315T, S315I, and S315R). Simulation studies indicate that of the three compounds, C-50 exhibited minimal deviation...

Tuberculosis (Edinburgh, Scotland), Jul 1, 2017

Recent studies in addition to studies based on whole genome sequencing (WGS) of clinical isolates... more Recent studies in addition to studies based on whole genome sequencing (WGS) of clinical isolates of Mycobacterium tuberculosis (MTB) from diverse geographical regions have provided useful insights into the mechanisms of drug resistance. Of importance, are some of the findings pertaining to mechanisms of resistance to two of the first-line anti-tuberculosis (TB) drugs, namely, rifampicin (RIF) and pyrazinamide (PZA). For example, the implication of mutations in rpoA and rpoC genes that act as compensatory mutations for those in the rpoB gene with respect to RIF resistance is noteworthy. Similarly, in the case of PZA resistance, the role of rpsA and panD genes has recently been noted. This highlights the evolving knowledge of resistance to these drugs. The present article provides a detailed account of the molecular mechanisms of resistance against two sterilizing first line anti-TB drugs (RIF and PZA) as well as an overview of sequence-based methods for detection of resistance to th...

Infection, Genetics and Evolution, 2016

The tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) and is considered a... more The tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) and is considered a worldwide public health problem, classified as the leading cause of death by a single infectious agent. The conventional treatment is performed through the combination of drugs that exhibit precocious or sterilizing bactericidal activity. The commonly used drugs (knowing as first line drugs) are: izoniazide (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (ETH). However, the number of resistant TB cases (classified as RR-TB, MDR-TB and XDR-TB) to drugs has been growing in concern over the years. Of the total cases registered in 2016, about 600 thousand were resistant to one or more drugs used in the treatment. Resistance of Mtb strains to antituberculosis drugs is closely related to mutations in different bacillus genes. Multidrugresistant tuberculosis is a worldwide problem. A better understanding of the molecular mechanisms associated with the resistance to first-line drugs used in the TB treatment is of great importance for the development of new drugs, directly helping to reduce the number of resistant cases and bringing great benefits to public health. A review of the mechanisms of action of first-line drugs used in the treatment regimen to sensitive tuberculosis, as well as the main associated resistance mechanisms are.

International Journal on Applied Bio-Engineering, 2007

Journal of Molecular Graphics and Modelling, 2016

Highlights  Rifampicin (RIF) an essential first-line anti-tuberculosis (TB) drug, resistance to ... more Highlights  Rifampicin (RIF) an essential first-line anti-tuberculosis (TB) drug, resistance to RIF is a potential threat to TB control program and widely considered as surrogate marker for detection of multi-drug resistant-TB (MDR-TB),  Mutations at RIF resistance-determining region (RRDR) of 81-bp in the rpoB gene coding for beta subunit or RpoB is the major cause of RIF resistance in Mycobacterium tuberculosis (MTB). Mutation at positions 526 and 531 are generally associated with high-level RIF resistance and at codons 516, 521 and 533 with low-level resistance.  In the present study, to understand the differences in binding ability between the wild type (WT) and mutant (MT) such as D516V, L521M, H526D, H526R, H526Y, S531L and L533P-RpoB proteins associated with RIF resistance in MTB; these proteins were modelled, docked and simulated using in silico approaches in comparison to WT.  Molecular modelling was performed with crystal structures of 4KBM and 2A68 as templates, using that WT and seven MTs of RpoB from MTB were generated.  Molecular docking between models of RpoB proteins and RIF was carried out, which showed higher values for WT compared to MTs. The high score in WT and MT-L521M may be due to the presence of favorable interactions with RIF which lacks in other MTs.  Molecular dynamics (MD) simulation suggest that the root mean square deviation (RMSD) was more and root mean square fluctuation (RMSF) was less in WT compared to MTs. Hydrogen bond interactions at RIF binding site from MD simulations were found comparatively lower in WT than MTs. All MTs demonstrated certain (2 Å) degree of structural deviation from the WT.  In short, these results suggest that RIF binding ability shows differences between WT and MTs, which could be because of different substitutions affecting the conformation of the MT proteins, leading to changes in binding interactions with RIF, eventually to the cause of RIF resistance.

Chemical Biology & Drug Design, 2016

Drug-resistant tuberculosis (DR-TB) is a serious problem that impedes the success of the TB contr... more Drug-resistant tuberculosis (DR-TB) is a serious problem that impedes the success of the TB control program. Of note, multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB have certainly complicated the scenario. One of the possible strategies to overcome drug resistance in an economic and simple manner would involve modification of existing anti-TB drugs to obtain derivatives that can work on resistant TB bacilli. These may have improved half-life and increased bioavailability, be more efficacious, and serve as cost-effective alternatives, as compared to new drugs identified through conventional methods of drug discovery and development. Although extensive literature is available on the activity of various derivatives of first-line drugs (isoniazid, rifampicin and pyrazinamide) on drug-susceptible Mycobacterium tuberculosis (MTB), reports on the activity of derivatives on resistant MTB are very limited, to our knowledge. In light of this, the present review aims to provide a concise report on the derivatives of first-line drugs that have the potential to overcome the resistance to the parental drug and could thus serve as effective alternatives.

Pyrazinamide (PZA) - an important drug in the anti-tuberculosis therapy, activated by an enzyme P... more Pyrazinamide (PZA) - an important drug in the anti-tuberculosis therapy, activated by an enzyme Pyrazinamidase (PZase). The basis of PZA resistance in Mycobacterium tuberculosis (Mtb) is owing to mutation in pncA gene coding for PZase. The identification of the structural or functional defects in the mutant enzymes leading to resistance still remains an area to be explored. The Wild-type (WT) and five mutant models Asp8Gly, Lys96Thr, Ser104Arg, Cys138Ser and Cys138Tyr were docked with PZA and its derivatives. In the present study, docking results has aided in predicting the best form of PZA to bind with mutants of PZase to be compounds-10 and 4. These models represent the first in-silico evidence for the binding interaction of PZase with PZA derivatives/analogues. The models may provide useful chemical insights for designing new anti-TB agents in order to overcome the resistance developed with PZA.