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Ene-Reductases in Pharmaceutical Chemistry
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In the 1960s, fosfomycin (originally phosphonomycin, trade names Monurol and Monuril) was isolated by screening fermentation broths of Streptomyces fradiae within a collaborative project between Merck and the Spanish “Compañía Española de Penicilina y Antibióticos” (CEPA) (Hendlin et al., 1969). The compound exhibited broad antibacterial activity against Gram-positive as well as Gram-negative pathogens, and for more than 20 years, it has been used as an oral treatment for urinary tract infections (Silver, 2017). Due to its unique mode of action—inhibition of murein biosynthesis through irreversible interaction with enzyme MurA—fosfomycin makes cross-resistance uncommon and allows for synergies with other antibiotics (Falagas et al., 2016). In an era of antibiotic resistance and limited new treatment options, fosfomycin is of interest against multidrug-resistant (MDR) and extensively drug-resistant (XDR) nosocomial (hospital-acquired) infections, for which limited treatment options are available. Fosmidomycin, on the other hand, inhibits DXP reductoisomerase, a key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis, and thus is considered for treatment of malaria in combination with for example clindamycin (Ruangweerayut et al., 2008).
Impact of Integrated Omics Technologies for Identification of Key Genes and Enhanced Artemisinin Production in Artemisia annua L.
Published in Tariq Aftab, M. Naeem, M. Masroor, A. Khan, Artemisia annua, 2017
Shashi Pandey-Rai, Neha Pandey, Anjana Kumari, Deepika Tripathi, Sanjay Kumar Rai
Overexpression of key biosynthetic genes is a promising approach for greater synthesis of product AN, and great success has been achieved in this direction via engineering almost all the key genes of the AN biosynthetic pathway. Two important key enzymes are HMG-CoA reductase (HMGR) and DXP reductoisomerase (DXR), which regulate the upstream pathway of AN biosynthesis (as represented in Figure 10.2) and act as initiators for isoprenoid biosynthesis. HMGR shunts HMG-CoA into the mevalonate pathway, whereas DXR, in the plastidic non-mevalonate pathway, catalyzes the first step of isoprenoid (C5) synthesis (Kiran et al. 2010). These two important key genes have been overexpressed in A. annua by many workers. Transfer of the Catharanthus roseus HMGR gene to A. annua, first reported by Aquil et al. (2009), resulted in 38.9% higher AN content in one of the transgenic lines.
Can Plasmodium’s tricks for enhancing its transmission be turned against the parasite? New hopes for vector control
Published in Pathogens and Global Health, 2019
S. Noushin Emami, Melika Hajkazemian, Raimondas Mozūraitis
Isoprenoids are widespread molecules and are necessary for all living organisms [58]. These molecules are involved in a vast spectrum of metabolic processes and serve as building blocks in the synthesis of various compounds such as cholesterol, steroid hormones and vitamins [59]. Animals, fungi and a few bacteria produce isoprenoids through a biosynthetic route called mevalonate pathway. By contrast, eubacteria, plastid-containing eukaryotes and most bacteria use an alternate metabolic route, the non-mevalonate or methylerythritol phosphate (MEP) pathway. Plants use both pathways, the chloroplast-localized MEP pathway that is used for biosynthesis of the terpene volatiles that contributs their characteristic flavors and fragrances [60]. MEP pathway is used by parasitic apicomplaxan protozoa, including Plasmodium (reviewed in [61]). The MEP pathway is one of the recognizable pathways in malaria parasite apicoplast and this pathway might have evolved due to its lower energy consumption (reviewed in [45]). Due to its non-host specificity, biochemical reactions of MEP pathway have been favored as a highlighted target for novel antiparasitic drugs in human host. For example, fosmidomycin and its derivative, FR-900098 have an antibiotic activity that targets DOXP reductoisomerase and inhibits the growth of asexual stage of malaria parasite [62]. Parasites lost their apicoplast after non-antifolate antibiotic treatments such as doxycycline. Interestingly, parasite growth (asexual stage) is rescued upon simultaneous supplementation with the central isoprenoid precursor, isopentenyl pyrophosphate (IPP) [63].
The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review
Published in Expert Review of Anti-infective Therapy, 2019
Thomas R Laws, Adam W. Taylor, Paul Russell, Diane Williamson
A multitude of small compounds have been considered as putative inhibitors of the Type III secretion system, and these are summarized below from two review articles [28,65]. However, to our knowledge, none of these compounds are in clinical use and would therefore require significant development prior to use in melioidosis patients. The only inhibitor of type III secretion that has been used in clinical trials is an antibody fragment (KB001-A) found to interact with the type III secretion system of P. aeruginosa [66]. Releases in the public media, however, revealed reported commercial concerns with regard to success criteria, and it has since been shelved. Variants of thiazolidinones (a class of small molecule that has been very useful in drug discovery [67]) have been used clinically for unrelated purposes (rosiglitazone and pioglitazone, which are both insulin sensitizers); however, it is clear that the structure of these molecules can to be optimized for effect in inhibiting type III secretion systems in both bacteria from the genus Salmonella and Yersinia [68]. With regard to compounds that can inhibit type II fatty acid synthesis, Anthranilic acid has been used clinically previously [69] and has chemistry associated with other clinically used products. Indole-3-carbinol, which is similar (SB418001), has also been used clinically [70]. Also dithiolethiones have been studied in some detail, more so in the form of Oltipraz, which was tolerated in humans with some adverse effects [71]. 4-aminopyridime (or famridine) bears similarity to the aminopyridine that targets bacteria [72] and has been shown to be tolerated in a clinical trial [73]. The easiest fatty acid synthesis inhibitor to repurpose might be Isoniazid, which is already in clinical use for the treatment of Mycobacterium infection. Another drug that is worthy of investigation is fosmidomycin. This drug is currently used as an antimalarial and targets DXP reductoisomerase, a critical enzyme in the nonmevalonate pathway. This drug also targets this pathway in at least some Gram negative bacteria [74].