Identify old drugs as selective bacterial β‐GUS inhibitors by structural‐based virtual screening and bio‐evaluations

Abstract

Irinotecan (CPT‐11) is a cytotoxic drug that has wide applicability and usage in cancer treatment. Despite its success, patients suffer dose‐dependent diarrhea, limiting the drug's efficacy. No effective therapy is available for this unmet medical need. The bacterial β‐glucuronidase (β‐GUS) plays pivotal role in CPT‐11‐induced diarrhea (CID) via activating the non‐toxic SN‐38G to toxic SN‐38 inside intestine. By using structural‐based virtual screening, three old drugs (N‐Desmethylclozapine, Aspartame, and Gemifloxacin) were firstly identified as selective bacterial β‐GUS inhibitors. The IC50 values of the compounds in the enzyme‐based and cell‐based assays range from 0.0389 to 3.6040 and 0.0105 to 5.3730 μM, respectively. The compounds also showed good selectivity against mammalian β‐GUS and no significant cytotoxicity in bacteria. Molecular docking and molecular dynamics simulations were performed to further investigate the binding modes of compounds with bacterial β‐GUS. Binding free energy decomposition revealed that the compounds formed strong interactions with E413 in catalytic trail from primary monomer and F365′ on the bacterial loop from the other monomer of bacterial β‐GUS, explaining the selectivity against mammalian β‐GUS. The old drugs identified here may be used as bacterial β‐GUS inhibitors for CID or other bacterial β‐GUS‐related disorders.

Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes

“…26 For example, pyrazolo [4,3-c]quinoline derivatives (TCH-3562) and uronic isofagomine derivatives could reduce CPT-11-induced complications without impairing its efficacy. [27][28][29] Reducing CPT-11 toxicity could in turn increase patients' tolerance to higher dosage, leading to better therapeutic outcomes. 30 This example illustrates the reciprocal interactions between commensal bacteria and chemotherapy, demonstrating the potential of microbiota modulation in reducing therapeutic toxicity and enhancing efficacy.…”

“…Selective β-glucuronidase inhibitors have now been developed to prevent CPT-11-induced microbial alteration and epithelial damage 26. For example, pyrazolo[4,3-c]quinoline derivatives (TCH-3562) and uronic isofagomine derivatives could reduce CPT-11-induced complications without impairing its efficacy 27–29. Reducing CPT-11 toxicity could in turn increase patients’ tolerance to higher dosage, leading to better therapeutic outcomes 30.…”

The Role of Gut Microbial β-Glucuronidase in Estrogen Reactivation and Breast Cancer

“…Another study also showed that gmGUS with loop 1 structure could process SN38-G more effectively than other types, based on which, the loop 1-targeted GUS inhibitor UNC10201652 was synthesized and showed great activities in blocking irinotecaninduced intestinal damage (Bhatt et al, 2020). In this regard, structure-based high-throughput screening may be a useful strategy for gmGUS inhibitor development (Wallace et al, 2010;Dashnyam et al, 2018;Feng et al, 2018;Chen et al, 2020;Jariwala et al, 2020).…”

Microbiota-Host-Irinotecan Axis: A New Insight Toward Irinotecan Chemotherapy

“…They found that nialamide, isocarboxazid, phenelzine, amoxapine, and mefloquine had significant inhibitory activity in vitro , respectively ( Ahmad et al., 2012 ). Three older drugs (aspartame, N-desmethylclozapine and gemifloxacin) have also been shown to have β-glucuronidase inhibitory activity using enzyme-based assays ( Chen et al., 2020 ). In vivo studies have indicated that amoxapine alleviates CPT11 toxicity and enhances the anti-tumor efficacy (to a certain extent) in tumor-bearing mice, and that the pharmaceutical activity of CPT11 is associated with its inhibitory impact on β-glucuronidase from E. coli , Enterococcus spp., Streptococcus spp., Escherichia spp., and Staphylococcus spp.…”