Proposed Mechanism of Antibacterial Activity of Glutathione by Inhibition of the d -Alanyl- d -alanine Carboxypeptidase
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Proposed Mechanism of Antibacterial Activity of Glutathione by Inhibition of the d‑Alanyl‑d‑alanine Carboxypeptidase Enzyme Dewi Mustikaningtyas1,3 · Sri Widyarti2 · Muhaimin Rifa’i2 · Nashi Widodo2 Accepted: 22 October 2020 © Springer Nature B.V. 2020
Abstract Several reports have suggested that glutathione (GSH) has antibacterial activity. However, the mechanism by which GSH inhibits microbial growth is a mystery. GSH has a structure similar to the antibiotic precursors of Penicillium that work as inhibitors of the d-alanyl-d-alanine-carboxypeptidase (DacC) enzyme. DacC catalyzes glycopeptides (d-alanyl-alanine) to form peptidoglycan in cell walls. Our objective was to study the potential mechanism of GSH as an inhibitor of the DacC enzyme in silico. Then, its activity that inhibited the growth of Salmonella typhi in vitro was tested. The binding affinity between GSH and DacC was examined by molecular docking. The pharmacophore of GSH was evaluated by Molinspiration and SwissADME. The stability of the GSH–DacC complex was measured by molecular dynamics, whereas antibacterial activity was examined by the disk diffusion and dilution methods, and then by scanning electron microscopy. The results indicate that GSH has the same ability as ampicillin in binding to the active site of DacC. GSH is capable of inhibiting the growth of S. typhi in vitro and is even known to cause cell wall damage. absorption, distribution, metabolism, and excretion predictions indicate that the properties of GSH are comparable to those of ampicillin. GSH is assumed to exert antibacterial activity by inhibiting the DacC enzyme, which might inhibit bacterial cell wall synthesis. Keywords Antibacterial · Glutathione · Transpeptidase inhibitor · Penicillin-binding protein · Molecular docking · Scanning electron microscopy
Introduction In 2000, it was estimated that there were 2.16 million cases of typhoid fever in Asia and around 216,000 people died (Crump et al. 2004). Cases of typhoid fever caused by bacterial Salmonella typhi infection are still often found in Indonesia. Until 2008, the incidence rate of typhoid was 180.3 per 100,000 people annually in Indonesia (Ochiai (2008)). Up to 2016, typhoid fever was among the top ten foodborne diseases in Indonesia (Afifah and Pawenang 2019). The handling of infectious diseases has always relied on antibiotics. * Sri Widyarti [email protected] 1
Doctoral Program of Biology, Faculty of Mathematics and Natural Science, Brawijaya University, Malang, Indonesia
2
Biology Department, Faculty of Mathematics and Natural Science, Brawijaya University, Malang, Indonesia
3
Biology Department, Faculty of Mathematics and Natural Science, Universitas Negeri Semarang, Semarang, Indonesia
One of the four mechanisms by which an antibiotic acts is through the inhibition of cell wall synthesis. Antibiotics that work by inhibiting cell wall synthesis include the β-lactam antibiotics (Kapoor et al. 2017), which are wellknown inhibitors of d-alanyl-d-alanine-carboxypeptidase (DacC) (Frere and Page 2014). D
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