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Bioengineering of Inorganic Nanoparticle Using Plant Materials to Fight Extensively Drug-Resistant Tuberculosis
Published in Richard L. K. Glover, Daniel Nyanganyura, Rofhiwa Bridget Mulaudzi, Maluta Steven Mufamadi, Green Synthesis in Nanomedicine and Human Health, 2021
Mpho Phehello Ngoepe, Maluta Steven Mufamadi
Mycobacterial cell wall mycolic acids, mannose and lactose have become one of the leading ligands for targeted drug delivery for TB management (Costa-Gouveia et al., 2017). Apart from target delivery, pharmaceutical agents can also be added to the surface of the nanoparticle. In the field of drug delivery, nanoparticles can serve as carriers of drugs either through encapsulation or surface conjugation where drug release is stimulated by an external (light, ultrasound or magnetic field) or internal stimuli (pH, redox balance or temperature changes) (Le et al., 2019). When functionalizing inorganic nanoparticles, various antibiotics such as ciprofloxacin have been conjugated to zinc oxide nanoparticles whilst ampicillin, kanamycin, streptomycin, gentamycin, neomycin have been conjugated to gold nanoparticles (AuNPs) against bacterial infections (Singh et al., 2020). A recent study has also shown the use of tetracycline as a co‐reducing and stabilizing agent for the synthesis of silver and gold nanoparticles, with killing effect against both gram‐negative and gram‐positive tetracycline‐susceptible and tetracycline‐resistant bacteria (Djafari et al., 2016). By combining gold nanoparticles with a multiblock copolyester, Gajendiran and colleagues showed that multi-TB drugs (isoniazid, rifampicin and pyrazinamide) could be released over a period of 264 hours (Gajendiran et al., 2016).
Role of Plant-Based Bioflavonoids in Combating Tuberculosis
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Assessment of Medicinal Plants for Human Health, 2020
Alka Pawar, Yatendra Kumar Satija
Mycobacterial cell wall is basically composed of three layers, namely: mycolic acid, arabinogalactan, and peptidoglycan. Fatty acids are essential component of mycolic acid layer. Additionally, fatty acids also serve as major source of bacterial energy. Therefore, targeting biosynthesis of fatty acids holds tremendous potential for anti-mycobacterial drug development.80 Reports have shown that bioconstituents in green tea prohibit specific reductases, FabG and FabI, which are involved in synthesis of bacterial type II fatty acids.84 It also hinders production of toxic metabolites by bacteria.60
Microorganisms
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Ursula Altmeyer, Penelope Redding, Nitish Khanna
The cell wall architecture of mycobacteria is characterized by the presence of mycolic acid, which is found in high concentrations in the waxy hydrophobic outer layer of the cell wall. Arabinogalactan connects this outer layer with an inner peptidoglycan layer. This makes the entire cell wall significantly thicker than that of either Gram negative or Gram positive organisms and conveys its typical staining properties of ‘acid and alcohol fastness’.
New therapeutic strategies for Mycobacterium abscessus pulmonary diseases – untapping the mycolic acid pathway
Published in Expert Review of Anti-infective Therapy, 2023
Matthéo Alcaraz, Thomas E. Edwards, Laurent Kremer
Mycolic acids (MA) represent crucial elements of the mycobacterial cell wall. They are homologous series of C60–90 α-alkyl β-hydroxy fatty acids and are primarily found as esters of the non-reducing arabinan terminus of arabinogalactan [25] and as extractable free lipids within the cell wall, mainly associated with trehalose to form trehalose dimycolates (TDM) [26]. MA are the primary targets of isoniazid (INH) and ethionamide (ETH) in Mtb, two drugs largely used for the treatment of TB. However, clinically used drugs against Mabs infections hitting the MA pathway are not available yet, though recent studies have emphasized that this metabolic pathway represents an excellent niche for druggable targets in Mabs. This is exemplified by the large number of hit compounds inhibiting the MA transporter MmpL3 [23,27,28] or the enoyl-ACP reductase InhA of the type II fatty acid synthase (FAS-II) [29], leading to the arrest of MA biosynthesis and mycobacterial cell death. This has raised strong interest in both MmpL3 and InhA as attractive targets for future drug development against Mabs lung diseases. In this review, we present recent research on inhibitors of the MA pathway in Mabs and discuss how this may be further exploited as alternative approaches to enhance treatment outcomes and reduce the burden on the patient produced by drug-associated side effects.
In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Pran Kishore Deb, Nizar A. Al-Shar’i, Katharigatta N. Venugopala, Melendhran Pillay, Pobitra Borah
In this study, the C-terminal thioesterase (TE) domain of the mycobacterial Polyketide synthase (Pks13) enzyme (Pks13-TE) has been identified as a putative target for the tested compounds. Biologically, the Pks13 enzyme catalyses the last condensation reaction of mycolic acid biosynthesis yielding an oxo‐mycolic acid intermediate which is then reduced to form a mature mycolic acid by a mycolyl reductase97,98,114. Mycolic acids, long α-alkyl-β-hydroxy fatty acids comprising 60–90 carbon atoms, are essential components of the mycobacterial cell wall and are also critical for mycobacterial persistence and pathogenesis115. The majority of mycolic acids are covalently bound to arabinogalactan-peptidoglycan forming the cell wall mycolyl-arabinogalactan-peptidoglycan complex. Moreover, they are associated with outer cell envelope lipids including trehalose monomycolate (TMM), trehalose dimycolate (TDM) and glucose monomycolate, also they can be found as free mycolic acids116,117. Given the prominent role of mycolic acids in mycobacterium cell viability and for virulence, enzymes involved in mycolic acids biosynthesis, such as Pks13, represent novel targets for drug development.
Development of novel isatin–nicotinohydrazide hybrids with potent activity against susceptible/resistant Mycobacterium tuberculosis and bronchitis causing–bacteria
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zainab M. Elsayed, Wagdy M. Eldehna, Marwa M. Abdel-Aziz, Mahmoud A. El Hassab, Eslam B. Elkaeed, Tarfah Al-Warhi, Hatem A. Abdel-Aziz, Sahar M. Abou-Seri, Eman R. Mohammed
On account of their superior anti-mycobacterial activity, compounds 5g and 5h were selected for further in silico investigation to explore their possible molecular target. Two promising drug enzymes in M. tuberculosis were suggested as potential targets for the target compounds in this study; the flavoenzyme Decaprenylphosphoryl-β-D-Ribose 2′-Epimerase (DprE1) and the enoyl-acyl carrier protein reductase (InhA) enzymes. Both enzymes play an essential role in the metabolism of the cell wall and the synthesis of mycolic acid, respectively30,31. The selection of these two enzymes is based on a pilot docking study that explored the plausible binding interactions and energy scores for the prepared compounds with different enzyme targets.