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Biochemistry
Published in Ronald Fayer, Lihua Xiao, Cryptosporidium and Cryptosporidiosis, 2007
Similar to other apicomplexans, Cryptosporidium is unable to synthesize purines de novo. However, its purine scavenge pathway is highly streamlined and appears to solely rely on uptake of adenosine from host through a transporter (Figure 3.1). Adenosine is converted to AMP by an adenosine kinase (AK) (Galazka et al., 2006), which in turn is converted to IMP (by AMP deaminase, [AMPDA]), XMP (by IMP dehydrogenase [IMPDH]), and GMP (by GMP synthase [GMPS]). However, unlike other apicomplexans, Cryptosporidium lacks a gene encoding hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT), indicating that GMP may only be made via a simple AMP-to-GMP pathway (Abrahamsen et al., 2004; Striepen and Kissinger, 2004). More surprisingly, CpIMPDH differs from other apicomplexan IMPDHs and is evolutionarily related to ε-proteobacterial homologues (Striepen et al., 2002; Umejiego et al., 2004). For this reason, CpIMPDH is much less sensitive to mycophenolic acid (MPA) than other eukaryotic homologues, including TgIMPDH. In fact, the CpIMPDH gene was first identified unexpectedly by complementation screening of a C. parvum expression library in a ΔHXGPRT strain of T. gondii (Striepen et al., 2002). The assay was originally designed to hunt for the hypothetical CpHXGPRT gene under the selection by MPA. More recently, this enzyme has been expressed as a recombinant protein, and its enzyme kinetics were characterized in detail (Umejiego et al., 2004). Additionally, CpIMPDH was also able to complement the function in an IMPDH-knockout strain of Escherichia coli, which not only confirms the function of this enzyme, but also makes it possible to perform bacterial growth-based high-throughput screening of anti-CpIMPDH compounds for drug development (Umejiego et al., 2004).
Simvastatin enhanced antimicrobial effect of Ag+ against E. faecalis infection of dentine through PLGA co-delivery submicron particles
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Wei Fan, Mengting Duan, Qing Sun, Bing Fan
In this study, the synergistic antibacterial effect of Ag++simvastatin was tested by three methods, MIC/MBC test, CFU counting and dynamic growth curve results confirmed synergistic antibacterial effect between Ag+ and simvastatin. The mechanism behind the bactericidal effect of Ag+ is reported to be the interaction with the bacterial cell envelope (destabilization of the membrane—loss of K+ ions and decrease of ATP level, bonded with phospholipids) and deactivation of metabolism-related molecules inside the cell (e.g. nucleic acids and enzymes) [19]. Despite this, many bacteria have developed the resistant ability against Ag+, through its active efflux system or extracellular polymeric substances (EPS) [19]. Simvastatin is a specific competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-COA) inhibitor inhibiting the synthesis of endogenous cholesterol [6]. It has been reported that simvastatin could reduce the production of EPS of bacteria [7]. Furthermore, simvastatin was also found to be able to reduce the ADK (Adenosine Kinase) gene expression of methicillin-resistant Staphylococcus aureus (MRSA), which is closely related to the energy and the heavy ion efflux activity of bacteria [6,20,21]. All these could possibly explain the synergistic antibacterial effect between Ag+ and simvastatin. Besides, this study also revealed that simvastatin had slight antibacterial effect against E. faecalis, but the MIC of simvastatin could not be detected.