Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target

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.

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714: Inhibition of Bladder Cancer Cell Proliferation by Mycobacterial Cell Wall-DNA Complex (MCC) in Combination with Chemotherapeutic Agents

The Journal of Urology ◽

10.1016/s0022-5347(18)37963-1 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 190-190

Author(s):

Myriam Labelle ◽

Mario C. Filion ◽

Nigel C. Phillips

Keyword(s):

Cell Proliferation ◽

Bladder Cancer ◽

Cell Wall ◽

Cancer Cell ◽

Chemotherapeutic Agents ◽

Bladder Cancer Cell ◽

Cancer Cell Proliferation ◽

Mycobacterial Cell ◽

Mycobacterial Cell Wall ◽

Dna Complex

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AN EXHAUSTIVE REVIEW ON EMERGING DRUG TARGETS OF TUBERCULOSIS WITH SPECIAL EMPHASIS ON CELL WALL SYNTHESIS

Innovare Journal of Life Sciences ◽

10.22159/ijls.2021.v9i5.42000 ◽

2021 ◽

pp. 1-7

Author(s):

SNEHAL R THAKAR ◽

DEEPALI A BANSODE

Keyword(s):

Cell Wall ◽

Genetic Information ◽

Drug Targets ◽

Drug Candidate ◽

Drug Resistant ◽

Mortality And Morbidity ◽

Mycobacterial Cell ◽

Causes Of Mortality ◽

Mycobacterial Cell Wall ◽

Novel Drug

Tuberculosis (TB) is one of the top 10 causes of mortality and morbidity. Worldwide, yet, it has been over 60 years since a novel drug was introduced in market to treat the disease exclusively. Increased number of drug resistant TB cases has prompted the search for novel potent anti-TB drug. Mycobacterial cell wall has unique structure which provides integrity to the cell. The future development of new potent anti-TB drug targets is associated with the synthesis of various cell wall constituents; the structural and genetic information about mycobacterial cell wall envelope is now available. In the present review, we have focused on prospective drug targets that can be optimum triumph for successful drug candidate.

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Potential Drug Targets in Mycobacterial Cell Wall: Non-Lipid Perspective

Current Drug Discovery Technologies ◽

10.2174/1570163815666180605113609 ◽

2020 ◽

Vol 17 (2) ◽

pp. 147-153

Author(s):

Shrayanee Das ◽

Saif Hameed ◽

Zeeshan Fatima

Keyword(s):

Cell Wall ◽

Drug Targets ◽

Cell Structure ◽

Front Line ◽

New Drug ◽

Mycobacterial Cell ◽

Future Drug ◽

Mycobacterial Cell Wall ◽

Potential Drug Targets ◽

Wall Components

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB), still remains a deadly disease worldwide. With prolonged usage of anti-TB drugs, the current therapeutic regimes are becoming ineffective, particularly due to emergence of drug resistance in MTB. Under such compelling circumstances, it is pertinent to look for new drug targets. The cell wall envelope of MTB is composed of unique lipids that are frequently targeted for anti-TB therapy. This is evident from the fact that most of the commonly used front line drugs (Isoniazid and Ethambutol) act on lipid machinery of MTB. Thus, despite the fact that much of the attention is towards understanding the MTB lipid biology, in search for identification of new drug targets, our knowledge of bacterial cell wall non-lipid components remains rudimentary and underappreciated. Better understanding of such components of mycobacterial cell structure will help in the identification of new drug targets that can be utilized on the persistent mycobacterium. This review at a common platform summarizes some of the non-lipid cell wall components in MTB that have potential to be exploited as future drug targets.

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

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210727165742 ◽

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.

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An Insight into the Current Perspective and Potential Drug Targets for Visceral Leishmaniasis (VL)

Current Drug Targets ◽

10.2174/1389450121666200422083735 ◽

2020 ◽

Vol 21 (11) ◽

pp. 1105-1129

Author(s):

Rani Mansuri ◽

Jagbir Singh ◽

Anupama Diwan

Keyword(s):

Drug Targets ◽

Redox Homeostasis ◽

World Health ◽

Metabolism Pathway ◽

Thiol Metabolism ◽

Development Of Resistance ◽

Current Perspective ◽

Fatal Form ◽

Novel Target ◽

Health Organization

Leishmaniasis is one of the six entities on the list of most important diseases of the World Health Organization/Tropical Disease Research (WHO/TDR). After Malaria, it is one of the most prevalent and lethal parasitic diseases. VL is the fatal form of this disease, especially if left untreated. The drugs that are currently available for the treatment of VL are expensive, toxic, or no longer effective, especially in endemic regions. Currently, no vaccine has been developed to immunize humans against VL. The major problems with the current drugs are the development of resistance and their adverse effects. Therefore, there is a strong urge to research and design drugs that have better efficacies and low toxicities as compared to current chemotherapeutic drugs. Leishmania has various enzymes involved in its metabolic pathways, which are unique to either the same genus or trypanosomatids, making them a very suitable, attractive and novel target sites for drug development. One of the significant pathways unique to trypanosomatids is the thiol metabolism pathway, which is involved in the maintenance of redox homeostasis as well as protection of the parasite in the macrophage from oxidative stress-induced damage. In this review the several pathways, their essential enzymes as well as the proposed changes in the parasites due to drug resistance have been discussed to help to understand the most suitable drug target. The thiol metabolism pathway is discussed in detail, providing evidence of this pathway being the most favorable choice for drug targeting in VL.

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