Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis

Bhat, Zubair Shanib; Rather, Muzafar Ahmad; Maqbool, Mubashir; Lah, Hafiz Ul; Yousuf, Syed Khalid; Ahmad, Zahoor

doi:10.1016/j.biopha.2017.09.036

Cited by 76 publications

(61 citation statements)

References 120 publications

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“…M. tuberculosis cell wall contributes to virulence and also confers resistance to various drugs. The enzymes involved in mycolic acids, arabinogalactan, and peptidoglycan biosynthesis are targets for various small molecules . INH, a member of the current regimen is a pro‐drug, activated by KatG (catalase peroxidase) and inhibits InhA, an enzyme involved in mycolic acid biosynthesis .…”

Section: Screening Approachesmentioning

confidence: 99%

“…The resistance against nitroimidazoles has been mapped to F420 related enzymes such as F 420 ‐dependent glucose‐6‐phosphate dehydrogenase ( fgd ), Rv3547 and F 420 ‐biosynthetic enzymes ( fbiA , fbiB , and fbiC ) . The other enzymes involved in mycolic acid biosynthesis are also being explored as drug‐targets . For example, polyketide synthase 13 (Pks13) performs a Claisen type condensation reaction between C26 fatty acid and meromycolic acid, thereby, resulting in the formation of α‐alkyl‐β‐ketoacids .…”

Section: Screening Approachesmentioning

confidence: 99%

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Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Dhiman

Singh

2018

IUBMB Life

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Tuberculosis (TB) is a leading cause of mortality and morbidity with an estimated 1.7 billion people latently infected with the pathogen worldwide. Clinically, TB infection presents itself as an asymptomatic infection, which gradually manifests to life threatening disease. The emergence of various drug resistant strains of Mycobacterium tuberculosis and lengthy duration of chemotherapy are major challenges in the field of TB drug development. Hence, there is an urgent need to develop scaffolds that possess a novel mechanism of action, can shorten the duration of therapy, and are active against both drug resistant and susceptible strains. In this review, we will discuss recent progress made in the field of TB drug development with emphasis on screening methods and drug targets from M. tuberculosis. The current review provides insights into mechanism of action of new scaffolds that are being evaluated in various stages of clinical trials. © 2018 IUBMB Life, 70(9):905-916, 2018.

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Section: Screening Approachesmentioning

confidence: 99%

Section: Screening Approachesmentioning

confidence: 99%

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Dhiman

Singh

2018

IUBMB Life

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“…A branched polysaccharide; named as Arabinogalactan, connects the peptidoglycan with the outer layer of mycolic acid. Some unique glycosyltransferases are involved in the cell wall assembly (Bhat et al, 2017). The unique structure of the cell wall plays an important role in the survival of Mycobacterium , while it enters into non-replicative growth throughout dormancy (Alderwick et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…has been developed in recent years (Lata et al, 2007; Sharma et al, 2013; Dhanda et al, 2017; Agrawal et al, 2018; Kumar et al, 2018; Usmani et al, 2018a). Mycobacterium , neither Gram-positive nor Gram-negative, has unusual waxy coating (primarily of mycolic acid) on the cell surface, being dissimilar to other bacteria (Bhat et al, 2017; Squeglia et al, 2018; Velayati et al, 2018). The distinguish characteristic of Mycobacterium make them inappropriate for universal anti-bacterial peptide prediction methods.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Antitubercular Peptides From Sequence Information Using Ensemble Classifier and Hybrid Features

2018

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Tuberculosis is one of the leading cause of death worldwide, particularly due to evolution of drug resistant strains. Antitubercular peptides may provide an alternate approach to combat antibiotic tolerance. Sequence analysis reveals that certain residues (e.g., Lysine, Arginine, Leucine, Tryptophan) are more prevalent in antitubercular peptides. This study describes the models developed for predicting antitubercular peptides by using sequence features of the peptides. We have developed support vector machine based models using different sequence features like amino acid composition, binary profile of terminus residues, dipeptide composition. Our ensemble classifiers that combines models based on amino acid composition and N5C5 binary pattern, achieves highest Acc of 73.20% with 0.80 AUROC on our main dataset. Similarly, the ensemble classifier achieved maximum Acc 75.62% with 0.83 AUROC on secondary dataset. Beside this, hybrid model achieves Acc of 75.87 and 78.54% with 0.83 and 0.86 AUROC on main and secondary dataset, respectively. In order to facilitate scientific community in designing of antitubercular peptides, we implement above models in a user friendly webserver (http://webs.iiitd.edu.in/raghava/antitbpred/).

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“…The putative essential genes at these loci may be divided into three groups with three members each based on their known or putative functions ( Table 2). Genes at loci II, VII, and VIII form the first group with functions in the biosynthesis of mycolic acids (MAs) or arabinogalactans (AGs) which form the outer layers of mycobacterial cell wall (Jankute et al, 2015;Bhat et al, 2017). MSMEG_2580 at locus II ( Figure 2B) encodes GcpE/IspG, an enzyme in the synthesis of isoprenoid, a key precursor for cellular components including those required for cell wall biosynthesis (Brown et al, 2010;Artsatbanov et al, 2012).…”

Section: Identification Of Essential Genes Near Mycotetop 2 Insertionmentioning

confidence: 99%

Construction and Use of Transposon MycoTetOP2 for Isolation of Conditional Mycobacteria Mutants

2020

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Mycobacteria are unique in many aspects of their biology. The development of genetic tools to identify genes critical for their growth by forward genetic analysis holds great promises to advance our understanding of their cellular, physiological and biochemical processes. Here we report the development of a novel transposon, MycoTetOP 2 , to aid the identification of such genes by direct transposon mutagenesis. This mariner-based transposon contains nested anhydrotetracycline (ATc)-inducible promoters to drive transcription outward from both of its ends. In addition, it includes the Escherichia coli R6Kγ origin to facilitate the identification of insertion sites. MycoTetOP 2 was placed in a shuttle plasmid with a temperature-sensitive DNA replication origin in mycobacteria. This allows propagation of mycobacteria harboring the plasmid at a permissive temperature. The resulting population of cells can then be subjected to a temperature shift to select for transposon mutants. This transposon and its delivery system, once constructed, were tested in the fast-growing model Mycobacterium smegmatis and 13 mutants with ATc-dependent growth were isolated. The identification of the insertion sites in these mutants led to nine unique genetic loci with genes critical for essential processes in both M. smegmatis and Mycobacterium tuberculosis. These results demonstrate that MycoTetOP 2 and its delivery vector provide valuable tools for the studies of mycobacteria by forward genetics.

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Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis

Cited by 76 publications

References 120 publications

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Prediction of Antitubercular Peptides From Sequence Information Using Ensemble Classifier and Hybrid Features

Construction and Use of Transposon MycoTetOP2 for Isolation of Conditional Mycobacteria Mutants

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