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Preservative Resistance
Published in Philip A. Geis, Cosmetic Microbiology, 2020
Oxidative stress induced by triclosan is the selective mechanism that can cause genetic bacterial mutations (64). In Gram-negative and Gram-positive bacteria as well as Mycobacteria, triclosan has been shown to have a specific target of antimicrobial action against an enzyme in the bacterial fatty acid biosynthetic pathway, NADH-dependent enoyl-[acyl carrier protein] reductase (FabI) and its homolog InhA (65). Exposing Escherichia coli and Staphylococcus aureus to triclosan resulted in FabI mutations in the fatty acid biosynthetic pathway that caused each of these organisms to become resistant to triclosan (66,67). Studies have shown that some mutations affecting InhA will also lead to the development of triclosan resistance in Mycobacterium smegmatis and Mycobacterium tuberculosis (68,69).
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
Ethionamide requires activation via mono-oxygenase enzyme, coded by ethA, for the formation of NAD adduct. Hence, it leads to the inhibition of NADH-dependent enoyl acyl carrier protein reductase. The emergence of ethionamide resistance is correlated with the ethA and inhA gene mutations.40
Mycobacterium tuberculosis – The Organism
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
This is a pro-drug requiring oxidative activation by the mycobacterial catalase-peroxidase enzyme KatG. The most frequent mutations determining isoniazid resistance occur in the katG gene, but resistance is also due to mutations in the inhA locus or its promoter region and in the intergenic region of the oxyR-ahpC locus. The inhA locus codes for the enzyme enoyl-acyl carrier protein reductase are involved in mycolic acid synthesis and is a target for isoniazid. The oxyR-ahpC locus is, like the katG locus, involved in protection against oxidative stress, but it is not clear why mutations in this locus cause resistance to isoniazid. In addition, mycobacteria possess a polymorphic arylamine N-acetyltransferase enzyme involved in mycolic acid synthesis that, by local acetylation of INH, may contribute to resistance to this agent [68]. The relative frequency of the various mutations conferring resistance to isoniazid vary according to the genotypes, described earlier, of M. tuberculosis and therefore show geographical differences in their distribution [69].
Clostridioides difficile: innovations in target discovery and potential for therapeutic success
Published in Expert Opinion on Therapeutic Targets, 2021
Tanya M Monaghan, Anna M Seekatz, Benjamin H Mullish, Claudia C. E. R Moore-Gillon, Lisa F. Dawson, Ammar Ahmed, Dina Kao, Weng C Chan
Fatty acids play a crucial role in the maintenance of the integrity of bacterial cell membranes, and their biosynthesis, as part of the non-mammalian type II fatty acid synthase (FASII) pathway, is mediated by a multitude of interlinked acyl carrier proteins (ACPs) in the cytoplasm [61,62]. Substrates of this pathway are bound to ACPs such as FabD, FabF and FabG, and undergo a series of reactions to extend their acyl chains; each elongation cycle is culminated by reduction, which is catalyzed by an enoyl-acyl carrier protein reductase. These enzymes thus serve as suitable antimicrobial targets, an example of which is isoniazid, an antibiotic used in treating Mycobacterium tuberculosis, and one which functions by inhibiting the reductase FabI [63]. Since bacterial species utilize specifically distinct enoyl-ACP reductases, its inhibition additionally provides a selective antimicrobial target. For instance, triclosan, another known FabI inhibitor, does not inhibit reductases such as FabK and FabV [64,65]. Although not as extensively studied as FabI, FabK has previously been reported as the sole reductase present in Streptococcus pneumoniae [66], and this has led to the identification of FabK inhibitors [67], including compounds derived from phenylimidazole [68].
Binding site comparisons for target-centered drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Novel scaffolds open new opportunities to medicinal chemists for the development of inhibitors with properties different from those already known [37]. Homology docking was used to extend the scaffold range of inhibitors of pathway II for the biosynthesis of mycobacterial fatty acids, which is an attractive target for the development of selective antimycobacterial agents [38]. The study focused on InhA, the key enzyme on this pathway, and an NADH-dependent enzyme enoyl-acyl carrier protein reductase targeted by isoniazid, the original antimycobacterial drug [39]. Almost 600 ligands were transferred to InhA, and eight were selected for experimental evaluation [38]. Those selected originated from proteins with low sequence identities (~30%) to the InhA enzyme and with different scaffolds than the known InhA inhibitors. Three active compounds were confirmed, 1-(3,4-dichlorobenzyl)-5,6-dimethyl-1H-benzo[d]imidazole being the most active with an IC50 value of 10 ± 2 μM. The three new InhA inhibitors had new scaffolds previously untested on InhA and represented good starting points for further optimization. The advantage of binding site comparison is that it allows the discovery from related research fields of new compounds, which were previously not considered as antimycotic agents.
Novel insights into the pharmacometabonomics of first-line tuberculosis drugs relating to metabolism, mechanism of action and drug-resistance
Published in Drug Metabolism Reviews, 2018
INH is considered a pro-drug, which passively diffuses through the mycobacterial cell wall, and once inside the M. tuberculosis, is activated by the catalase-peroxidase enzyme, KatG, a reaction supported by a range of oxidants, including superoxide, hydrogen peroxide and simple alkyl hydroperoxides (Timmins and Deretic 2006; Unissa et al. 2016). The subsequently generated isonicotinoyl radicals form covalent adducts with NAD+ (nicotinamide adenine dinucleotide), which in turn acts as a competitive inhibitor of InhA, a M. tuberculosis enoyl acyl carrier protein reductase involved in fatty acid oxidation via the FAS II (fatty acid synthesis pathway type 2) system, during mycolic acid synthesis (Figure 1) (Rawat et al. 2003). Since mycolic acids are the major structural components of the M. tuberculosis cell wall, INH-induced inhibition of mycolic acid synthesis will subsequently lead to a disruption in the cell wall structure, ultimately causing M. tuberculosis cell death. Furthermore, the reactive species generated during the course of INH activation, are also proposed to result in DNA, carbohydrate and lipid damage, and the inhibition of the NAD+ metabolism (Zhang 2005).