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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
Abdullah Alsultan, Charles A. Peloquin
Both INH and ETA are pro-drugs, requiring activation by mycobacterial cell processes prior to inhibition of mycolic acid synthesis [125,126]. The gene ethA, through the production of the flavin-containing mono-oxygenase EtaA, appears responsible for activation of ETA. Mutations in the ethA or ethR gene correlate with resistance to ETA [127]. Also, ETA activity is further influenced by the gene inhA, which is also associated with low-level INH resistance [126,128]. Mutations in genes encoding mycothiol (MSH) might confer resistance to both drugs [129]. This appears to explain the partial cross-resistance between ETA and INH.
Ethionamide and Prothionamide
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Mycobacteria have a similar inner lipid membrane and peptidoglycan cell wall to other bacteria but possess a second bilaminar outer component to their cell envelope, loosely analogous to the outer membrane of Gram-negative bacteria. However, its structure is asymmetric, with the inner component composed of molecules specific to the family Mycobacteriaceae: arabinogalactan and mycolic acids. Ethionamide interferes with the production of specific mycolic acids by first being activated to an ethionamide–NAD adduct, after which the adduct binds to and inhibits InhA (Wang et al., 2007). InhA is an NADH-dependent enoyl-ACP reductase of the type II fatty acid synthesis pathway that participates in the biosynthesis of mycolic acids. As its name suggests, InhA is also the molecular target of activated isoniazid (Banerjee et al., 1994; Vilcheze et al., 2005; Wang et al., 2007; Gurvitz et al., 2008; Vilcheze et al., 2008). Activation of ethionamide is mediated by a monooxygenase encoded by the gene ethA (DeBarber et al., 2000; Morlock et al., 2003; Wang et al., 2007), but activation of isoniazid is mediated by a catalase–peroxidase encoded by a different gene, katG (Zhang et al., 1992). The binding of NAD–ethionamide/isoniazid adducts to InhA is competitively inhibited by intracellular NADP. Mutations in inhA and its promoter, ethA and ethR explain most ethionamide resistance but other mechanisms exist, including alterations in NADH dehydrogenase, encoded by nph, that lead to increased levels of intracellular NADP and competition between NADP and activated drug (Miesel et al., 1998; Vilcheze et al., 2005). Another resistance mechanism for ethionamide was identified in the laboratory strain H37Rv linked to mutations in mshA. This gene encodes a protein involved in mycothiol production. Although failure to produce mycothiol was non-lethal, these cells are ethionamide resistant. It is assumed that mycothiol production is somehow linked to the activation of ethionamide (Vilcheze and Jacobs, 2007).
Insights into structures of imidazo oxazines as potent polyketide synthase XIII inhibitors using molecular modeling techniques
Published in Journal of Receptors and Signal Transduction, 2020
Shanthakumar B., Kathiravan M. K.
In continuation to our ongoing work on exploring theoretical studies to develop novel inhibitors [9] for tuberculosis targeting thymidine monophosphate kinase [10], mycothiol biosynthesis inhibitor [11], and carbonic anhydrase IX inhibitors [12], we herein report a QSAR and molecular docking studies on nitroimidazole oxazines derivatives as potent PKS inhibitors. The present study aimed to develop QSAR of novel fused 5/6 nitro hetero bicyclic ring systems for their PKS13 inhibitory activity and to rationalize the effect of substitution variation on the inhibitory activity of these derivatives. New chemical entities (NCEs) will be designed from the findings of key descriptor contribution and subject to the prediction of activity. To gain further insights, the docking studies will be performed on the designed series of NCEs with the crystal structure of PKS13.