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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).
Terpenes and Terpenoids
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Isoprene is made through the methylerythritol 4-phosphate pathway (MEP pathway, also called the nonmevalonate pathway) in the chloroplasts of plants. One of the two end products of the MEP pathway, DMADP, is catalyzed by the inside isoprene synthase to form isoprene. Therefore, an inhibitor that blocks the MEP pathway, such as fosmidomycin, also block isoprene formation. Isoprene emission increases dramatically with temperature and maximizes at around 40°C (Figure 8.1).
Synthesis and biological activity of iron(II), iron(III), nickel(II), copper(II) and zinc(II) complexes of aliphatic hydroxamic acids
Published in Journal of Coordination Chemistry, 2023
Ibrahima Sory Sow, Michel Gelbcke, Franck Meyer, Marie Vandeput, Mickael Marloye, Sergey Basov, Margriet J. Van Bael, Gilles Berger, Koen Robeyns, Sophie Hermans, Dong Yang, Véronique Fontaine, François Dufrasne
Compounds such as HA could inhibit microorganisms through metal chelation involved in enzymatic reactions but also through their ability to release HNO and NO, as shown in CV analysis [83]. Fosmidomycin, an antibiotic from Streptomyces, derived of N-hydroxyhexanamide, is a good example of a natural HA targeting a metal containing enzyme in bacteria. Indeed, it is able to inhibit DXP reductoisomerase whose activity depends on Mn2+, Co2+ or Mg2+ ions [84]. In the case of metal complexes, either small amount of metal arising from complex dissociation or the metal complexes themselves could produce deleterious biochemical effects on microorganisms. It remains difficult to determine precisely the mechanism of action of such species in complex biological systems, but it is logical to consider that metal ions could combine with the chemical groups present in proteins, mainly SH, COO- and imidazoles, such as those present in ribosomes [84]. Other hypotheses on the mode of action include inhibition of DNA synthesis, cell wall or membrane disruption or inhibition of RNA synthesis based on a disturbance in the energy metabolism of the cell. Finally, disruption of the membrane could affect the electron transport chain and the oxygen consumption of microorganisms. However, some compounds could also act outside the cytoplasm. Pathogens secrete various molecules (small ones or proteins) to achieve some metabolic pathways at the membrane periphery, as exemplified by bacterial transpeptidases that are inhibited by beta-lactam antibiotics.