Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Abstract

Colorectal cancer (CRC) ranks third among all cancers in terms of prevalence. There is growing evidence that gut microbiota has a role in the development of colorectal cancer. Fusobacterium nucleatum is overrepresented in the gastrointestinal tract and tumor microenvironment of patients with CRC. This suggests the role of F. nucleatum as a potential risk factor in the development of CRC. Hence, we aimed to explore whole genomes of F. nucleatum strains related to CRC to predict potential therapeutic markers through a pan-genome integrated subtractive genomics approach. In the current study, we identified 538 proteins as essential for F. nucleatum survival, 209 non-homologous to a human host, and 12 as drug targets. Eventually, riboflavin synthase (RiS) was selected as a therapeutic target for further processing. Three different inhibitor libraries of lead-like natural products, i.e., cyanobactins (n = 237), streptomycins (n = 607), and marine bacterial secondary metabolites (n = 1226) were screened against it. After the structure-based study, three compounds, i.e., CMNPD3609 (−7.63) > Malyngamide V (−7.03) > ZINC06804365 (−7.01) were prioritized as potential inhibitors of F. nucleatum. Additionally, the stability and flexibility of these compounds bound to RiS were determined via a molecular dynamics simulation of 50 ns. Results revealed the stability of these compounds within the binding pocket, after 5 ns. ADMET profiling showed compounds as drug-like, non-permeable to the blood brain barrier, non-toxic, and HIA permeable. Pan-genomics mediated drug target identification and the virtual screening of inhibitors is the preliminary step towards inhibition of this pathogenic oncobacterium and we suggest mouse model experiments to validate our findings.

Research trends on the relationship between gut microbiota and colorectal cancer: A bibliometric analysis

“…Recently, with improvements in culture media, emerging evidence indicates that some specific bacteria pathogens are closely associated with CRC, such as Fn , E. coli , ETBF and P. anaerobius ( Arthur et al., 2012 ; Kostic et al., 2013 ; Tsoi et al., 2017 ; Chung et al., 2018 ; Long et al., 2019 ; Pleguezuelos-Manzano et al., 2020 ). Fn has been a hot topic of research in recent years, with numerous studies conducted at the cellular level, at the animal level and on human specimens ( Kostic et al., 2013 ; Yang et al., 2017 ; Hashemi Goradel et al., 2019 ; Rubinstein et al., 2019 ; Xue et al., 2021 ; Alturki et al, 2022 ). In addition, researchers have identified beneficial probiotics such as Bifidobacterium and Lactobacillus that have anti-inflammatory properties and are capable of producing beneficial metabolites (e.g.…”

Can we microbe-manage our vitamin acquisition for better health?

“…Recently, roseoflavin, a riboflavin analogue, was found to inhibit the proliferation of the malaria parasite [ 50 ]. Also, riboflavin synthase was selected as a therapeutic target to inhibit gut microbes involved in the development of colorectal cancer [ 51 ].…”

Bacterial, Viral and Parasitic Pathogens and Colorectal Cancer

“…Because of a growing number of recent publications linking Fusobacterium nucleatum to CRC, Altruki et al developed the computational pipeline that will help in the identification of natural therapeutic products against the microbial targets [ 17 ]. They performed the high throughput screening of core genomes of 14 F. nucleatum strains related to CRC through a pan-genome integrated subtractive genomics approach and identified 12 loci as drug targets.…”