Exploring targets of cell wall protein synthesis and overexpression mediated drug resistance for the discovery of potential M. tb inhibitors

2021 ◽  
Vol 21 ◽  
Author(s):  
Sisir Nandi ◽  
Anil Kumar Saxena
Keyword(s):  
Drug Resistance ◽  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Drug Regimen ◽  
World Health ◽  
Tuberculosis Complex ◽  
Short Course ◽  
Directly Observed Treatment ◽  
Health Organization ◽  
Mycobacterial Cell Wall

: Tuberculosis is an infectious disease engulfing millions of lives worldwide; it is caused by mammalian tubercle bacilli, Mycobacterium tuberculosis complex which may consist of strains viz. M. tuberculosis hominis (human strain), M. microti, M. pinnipedii and M. canettii. The other pathogenic strain is M.africanum which belongs to the M. tuberculosis complex and it is fully virulent for humans. The non-pathogenic strains in the complex may include, M. fortuitum and M.smegmatis. Extensive research has been carried out to combat this dangerous disease. World Health Organization proposed Directly Observed Treatment Short-course regimen (DOTS) for the eradication of the TB. In addition, the compounds such as TBA-7371, TBI-166, AZD5847 and PBTZ-169 are under clinical trials whereas the recently FDA approved anti tubercular drugs are Pretomanid (PA-824), Bedaquiline (TMC207), Linezolid (PNU-100480) and Delamanid (OPC-67683). The early detection of mycobacterium tuberculosis can be permanently cured by DOTS comprising of Pyrazinamide (Z), Isoniazid (H), Rifampin (R) and Ethambutol (E). Duration of the treatment depends on viability of the disease. DOTS can target to disrupt the biosynthesis of mycobacterial cell wall proteins expressed by various genes. Overexpression of these genes may produce drug-resistant due to dose misuse or the intake of quality compromised anti tubercular drug regimen. Therefore, in the present review there has been a necessity to report the second line antitubercular chemotherapeutics to target various proteins which are the building block of M. tb cell wall, overexpression of which may produce drug resistance.

scholarly journals Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target

Parasitology ◽  
2016 ◽  
Vol 145 (2) ◽  
pp. 116-133 ◽  
Author(s):  
KATHERINE A. ABRAHAMS ◽  
GURDYAL S. BESRA
Keyword(s):  
Cell Wall ◽  
Drug Targets ◽  
Complex Structure ◽  
Supporting Cell ◽  
Chemotherapeutic Agents ◽  
World Health ◽  
Mycobacterial Cell ◽  
Clinical Drugs ◽  
Health Organization ◽  
Mycobacterial Cell Wall

SUMMARYMycobacterium tuberculosis(Mtb), the etiological agent of tuberculosis (TB), is recognized as a global health emergency as promoted by the World Health Organization. Over 1 million deathsperyear, along with the emergence of multi- and extensively-drug resistant strains ofMtb, have triggered intensive research into the pathogenicity and biochemistry of this microorganism, guiding the development of anti-TB chemotherapeutic agents. The essential mycobacterial cell wall, sharing some common features with all bacteria, represents an apparent ‘Achilles heel’ that has been targeted by TB chemotherapy since the advent of TB treatment. This complex structure composed of three distinct layers, peptidoglycan, arabinogalactan and mycolic acids, is vital in supporting cell growth, virulence and providing a barrier to antibiotics. The fundamental nature of cell wall synthesis and assembly has rendered the mycobacterial cell wall as the most widely exploited target of anti-TB drugs. This review provides an overview of the biosynthesis of the prominent cell wall components, highlighting the inhibitory mechanisms of existing clinical drugs and illustrating the potential of other unexploited enzymes as future drug targets.

scholarly journals Co-Management of Active Tuberculosis and Diabetes Mellitus Under Supervised DOTS Strategy—A Saudi Perspective

Reports ◽  
2018 ◽  
Vol 1 (3) ◽  
pp. 25
Author(s):  
Sarvath Ali ◽  
Marepalli Rao ◽  
Ahmed Sahly ◽  
Abdulazeez Alfageeh ◽  
Abdulrahman Bakari
Keyword(s):  
Diabetes Mellitus ◽  
Classification Tree ◽  
Healing Process ◽  
World Health ◽  
Health Concern ◽  
Global Public Health ◽  
Tb Treatment ◽  
Short Course ◽  
Directly Observed Treatment ◽  
Health Organization

Tuberculosis (TB) is a global public health concern, specifically in countries which have high prevalence of HIV/AIDS, malnutrition, unhygienic conditions, etc. Some evidence has been presented that diabetes mellitus (DM) is a risk factor for TB. On the other hand, among those who have DM, TB infection enhances glucose intolerance and worsens glycemic control. The combination of TB and DM, due to immuno-compromised status of DM, can delay the healing process of TB. The focus of this paper is the World Health Organization directly observed treatment, short course (DOTS) program implemented in Gazan province, Saudi Arabia, to treat TB. The data included some patients with both TB and DM. The data has been analyzed to assess how effective the DOTS program was in managing TB. It was found that DM was not a significant factor in the outcome of TB treatment. We used the same data and observed that the non-significance of DM is due to heterogeneity of patient population, Saudis and Non-Saudis. The prevalence of DM was very high among Saudis. This is understandable in view of different lifestyles. Non-Saudis are predominantly Yemenis. For Saudis, DM was indeed found to play a role in the treatment outcome of TB, after an application of a classification tree methodology on the data. This is the main focus of the paper.

Rapid Diagnosis of Mycobacterium tuberculosis Infection and Drug Susceptibility Testing

2013 ◽  
Vol 137 (6) ◽  
pp. 812-819 ◽  
Author(s):  
Michael L. Wilson
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Susceptibility Testing ◽  
Simultaneous Detection ◽  
Rapid Test ◽  
World Health ◽  
Tuberculosis Complex ◽  
Novel Technologies ◽  
Molecular Assays ◽  
Variable Sensitivity

Context.—The global control of tuberculosis remains a challenge from the standpoint of diagnosis, detection of drug resistance, and treatment. This is an area of special concern to the health of women and children, particularly in regions of the world with high infant mortality rates and where women have limited access to health care. Objective.—Because treatment can only be initiated when infection is detected, and is guided by the results of antimicrobial susceptibility testing, there recently has been a marked increase in the development and testing of novel assays designed to detect Mycobacterium tuberculosis complex, with or without simultaneous detection of resistance to isoniazid and/or rifampin. Both nonmolecular and molecular assays have been developed. This review will summarize the current knowledge about the use of rapid tests to detect M tuberculosis and drug resistance. Data Sources.—Review of the most recent World Health Organization Global Tuberculosis Report, as well as selected publications in the primary research literature, meta-analyses, and review articles. Conclusions.—To a large extent, nonmolecular methods are refinements or modifications of conventional methods, with the primary goal of providing more rapid test results. In contrast, molecular methods use novel technologies to detect the presence of M tuberculosis complex and genes conferring drug resistance. Evaluations of molecular assays have generally shown that these assays are of variable sensitivity for detecting the presence of M tuberculosis complex, and in particular are insensitive when used with smear-negative specimens. As a group, molecular assays have been shown to be of high sensitivity for detecting resistance to rifampin, but of variable sensitivity for detecting resistance to isoniazid.

scholarly journals Spread of HIV-1 infection affects tuberculosis control in Russia

2001 ◽  
Vol 5 (45) ◽  
Author(s):  
B Twisselmann
Keyword(s):  
World Health ◽  
Prevention Measures ◽  
Tuberculosis Control ◽  
Administrative District ◽  
Tb Control ◽  
Short Course ◽  
Rapid Spread ◽  
Directly Observed Treatment ◽  
Health Organization ◽  
Hiv 1

The rapid spread of HIV-1 infection in Russia has serious implications for the control of tuberculosis (TB) epidemics in the country, according to the authors of a research letter published in the Lancet (1). Aggressive prevention measures must be taken quickly if a public health disaster is to be avoided. Since October 1999, the administrative district (oblast) of Orel in Russia has been the site of a project for TB control by directly observed treatment, short course (DOTS) (http://www.who.int/gtb/dots/), organised by the World Health Organization (WHO).

scholarly journals Modal Sosial dan Partisipasi Masyarakat dalam Penemuan Penderita Tuberkulosis

2013 ◽  
Vol 7 (11) ◽  
pp. 495
Author(s):  
Reviono Reviono ◽  
Endang Sutisna Sulaeman ◽  
Bhisma Murti
Keyword(s):  
Social Capital ◽  
Death Rate ◽  
World Health ◽  
Crude Death Rate ◽  
Case Detection Rate ◽  
Short Course ◽  
Directly Observed Treatment ◽  
The One ◽  
Health Organization

Tuberkulosis merupakan masalah kesehatan masyarakat yang utama di tingkat global, regional, nasional, maupun lokal. World Health Organization menggulirkan strategi directly observed treatment short course (DOTS) dan strategi stop tuberculosis partnership bertujuan untuk menjangkau semua penderita tuberkulosis. Kedua strategi tersebut masih belum mampu mencapai target case detection rate (CDR) secara konsisten. Penelitian ini bertujuan merumuskan model modal sosial dan partisipasi masyarakat dalam crude death rate. Sasaran penelitian adalah petugas tuberkulosis dan kader di 30 desa di Kabupaten Karanganyar, Jawa Tengah. Metode yang digunakan adalah survei dan studi kasus. Hasil penelitian survei menunjukkan, desa dengan modal sosial yang tinggi mempunyai  kemungkinan untuk melampaui target CDR ≥ 70%, 9 kali lebih besar daripada desa dengan modal sosial rendah. Desa dengan partisipasi masyarakat tinggi mempunyai kemungkinan 7,5 kali lebih besar daripada desa dengan partisipasi masyarakat rendah. Hasil penelitian studi kasus menunjukkan, faktor-faktor modal sosial yang berhubungan dengan CDR terdiri dari dimensi kognitif meliputi kepercayaan dan merasa mempunyai program tuberkulosis. Dimensi relasional meliputi norma sosial, penanaman jasa pribadi, kerja sama, dan komunikasi. Dimensi struktural meliputi jejaring dan persatuan. Faktor-faktor partisipasi yang berhubungan dengan CDR meliputi identifikasi kebutuhan, menggerakan sumber daya program, dan kepemimpinan.Tuberculosis is an important public health problem of global, regional, national, and local levels. World health organization launched directly observed treatment short course (DOTS) and stop tuberculosis partnership strategies aiming to reach all tuberculosis patients. Both strategies have not been able to reach the case detection rate (CDR) target consistently. This research aimed to formulate a social capital and participation model in crude death rate. The target of research was the officers of tuberculosis programs and cadres in 30 villages in Karanganyar Regency, Central Java. The method used in this research was survey and case study. The result of survey research showed that the village with high social capital had 9 times probability of surpassing CDR target ≥ 70% than the one with low social capital and 7.5 times higher than the one with low public participation. The result of case study showed that the social capital factors relating to CDR consisted of cognitive dimension encompassing trust and sense of belonging to tuberculosis program. Relational dimension encompassed social norm, personal service implantation, cooperation, and communication. Structural dimension involved public network and association. The factors of participation relating to CDR included need identification, activating the program resource, and leadership.

scholarly journals Seventh WHO annual report on global TB control

2003 ◽  
Vol 7 (14) ◽  
Author(s):  
Keyword(s):  
Annual Report ◽  
Treatment Success ◽  
World Health ◽  
Tb Control ◽  
Short Course ◽  
The World ◽  
Control Programmes ◽  
Directly Observed Treatment ◽  
Health Organization ◽  
Share Information

To mark world TB day, 24 March 2003, the World Health Organization (WHO) has published the seventh annual report on global tuberculosis (TB) control. This report aims to share information from national TB control programmes, and includes data on case notifications and treatment outcomes. It also provides analysis of plans, finances and constraints on DOTS (directly observed treatment-short course) expansion for the 22 high burden countries in order to assess progress toward global targets for case detection (70%) and treatment success (85%).

scholarly journals World TB Day, 24 March 2003 and TB surveillance in Europe

2003 ◽  
Vol 7 (12) ◽  
Author(s):  
A Infuso ◽  
D Falzon ◽  
J Veen
Keyword(s):  
Treatment Outcome ◽  
Annual Report ◽  
World Health ◽  
Tuberculosis Control ◽  
Tb Control ◽  
Short Course ◽  
The World ◽  
Directly Observed Treatment ◽  
Health Organization ◽  
Standardised Patient

The theme of World TB day 2003 - "DOTS cured me – it will cure you too!" promotes the worldwide expansion of directly observed treatment-short course (DOTS), a multi pronged TB control strategy including the adoption of standardised patient management and the evaluation of treatment outcome of TB patients. Treatment outcome is a core surveillance indicator recommended to assess the implementation of DOTS. In recent years, DOTS has been adopted increasingly in European countries, especially in the East. The EuroTB annual report 2000 (in press, http://www.eurotb.org/) includes data on treatment outcome for TB cases notified in 1999 in 30 of the 51 countries of the World Health Organization (WHO) European Region. The WHO Global Tuberculosis Control report, available from 24 March 2003 at http://www.who.int/gtb/publications/globrep/index.html, contains current information on the DOTS situation in Europe and the rest of the world.

Medical interns knowledge of TB in Pakistan

2005 ◽  
Vol 35 (3) ◽  
pp. 144-147 ◽  
Author(s):  
J A Khan ◽  
S Zahid ◽  
R Khan ◽  
S F Hussain ◽  
N Rizvi ◽  
...  
Keyword(s):  
World Health ◽  
Teaching Hospitals ◽  
Effective Control ◽  
National Guidelines ◽  
Initiation Phase ◽  
Short Course ◽  
National Tuberculosis ◽  
Tuberculosis Programme ◽  
Directly Observed Treatment ◽  
Health Organization

Of 460 interns from five Pakistani teaching hospitals surveyed, only 22% correctly identified the estimated number of new TB cases in Pakistan. The majority (96%) knew that droplet infection was the usual mode of transmission. Only 38% considered sputum smears for acid-fast bacilli as the best test for diagnosis of pulmonary TB and 43.5% for follow-up during TB treatment. The recommended four-drug anti-TB regimen was prescribed by 56.5% in the initiation phase and the recommended two-drug combination in the continuation phase by 52%. Most interns (82%) were unable to identify a single component of directly observed treatment short course (DOTS) strategy. Our study reflects poor awareness of and low compliance to the World Health Organization/National Tuberculosis Programme guidelines among interns. For effective control of TB, immediate action to improve undergraduate and continuing medical education is essential, with special emphasis on national guidelines.

scholarly journals Application of Computational Methods in Understanding Mutations in Mycobacterium tuberculosis Drug Resistance

2021 ◽  
Vol 8 ◽  
Author(s):  
Grace Mugumbate ◽  
Brilliant Nyathi ◽  
Albert Zindoga ◽  
Gadzikano Munyuki
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Computational Methods ◽  
Drug Targets ◽  
Point Mutations ◽  
Machine Learning Techniques ◽  
World Health ◽  
Computational Techniques ◽  
Health Organization ◽  
Drug Resistant Strains

The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) impedes the End TB Strategy by the World Health Organization aiming for zero deaths, disease, and suffering at the hands of tuberculosis (TB). Mutations within anti-TB drug targets play a major role in conferring drug resistance within Mtb; hence, computational methods and tools are being used to understand the mechanisms by which they facilitate drug resistance. In this article, computational techniques such as molecular docking and molecular dynamics are applied to explore point mutations and their roles in affecting binding affinities for anti-TB drugs, often times lowering the protein’s affinity for the drug. Advances and adoption of computational techniques, chemoinformatics, and bioinformatics in molecular biosciences and resources supporting machine learning techniques are in abundance, and this has seen a spike in its use to predict mutations in Mtb. This article highlights the importance of molecular modeling in deducing how point mutations in proteins confer resistance through destabilizing binding sites of drugs and effectively inhibiting the drug action.

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