Pharmacomodulations of the benzoyl-thiosemicarbazide scaffold reveal antimicrobial agents targeting d-alanyl-d-alanine ligase in bacterio

Ameryckx, Alice; Pochet, Lionel; Wang, Gang; Yıldız, Esra; Saadi, Bouazza Es; Wouters, Jan; Bambeke, Françoise Van; Frédérick, Raphaël

doi:10.1016/j.ejmech.2020.112444

Cited by 25 publications

(13 citation statements)

References 69 publications

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“…The functionality of Ddl ligase depends on its ability to acquire ATP to catalyze reactions for maintaining the integrity of the bacterial cell wall, which makes it within the ATP-grasp enzyme superfamily [ 30 ]. While Ddl regions have previously been shown to be targeted by antibiotics [ 31 ], the diversity of the roles that ATP-grasp enzymes play in several metabolic pathways leaves several targets yet to be discovered.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary conservation of motifs within vanA and vanB of vancomycin-resistant enterococci

et al. 2022

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Background and Aim: Global Health is threatened by the rapid emergence of multidrug-resistant bacteria. Antibiotic resistomes rapidly evolve, yet conserved motifs elucidated in our study have the potential for future drug targets for precision medicine. This study aimed to identify conserved genetic sequences and their evolutionary pathways among vancomycin-resistant Enterococcus species such as Enterococcus faecium and Enterococcus faecalis. Materials and Methods: We retrieved a total of 26 complete amino acid and nucleotide sequences of resistance determinant genes against vancomycin (vanA and vanB), streptomycin (aac-aah), and penicillin (pbp5) from the publicly available genetic sequence database, GenBank. The sequences were comprised of bacteria classified under the genera of Enterococcus, Staphylococcus, Amycolatopsis, Ruminococcus, and Clostridium. Sequences were aligned with Clustal Omega Multiple Sequence Alignment program and Percent Identity Matrices were derived. Phylogenetic analyses to elucidate evolutionary relationships between sequences were conducted with the neighbor-end joining method through the Molecular Evolutionary Genetics Analysis (MEGAX) software, developed by the Institute of Molecular Evolutionary Genetics at Pennsylvania State University. Subsequent network analyses of the resistance gene, vanB, within E. faecium were derived from ScanProsite and InterPro. Results: We observed the highest nucleotide sequence similarity of vanA regions within strains of E. faecium (100%) and E. faecalis (100%). Between Enterococcus genera, we continued to observe high sequence conservation for vanA and vanB, up to 99.9% similarity. Phylogenetic tree analyses suggest rapid acquisition of these determinants between strains within vanA and vanB, particularly between strains of Enterococcus genera, which may be indicative of horizontal gene transfer. Within E. faecium, Adenosine 5'-Triphosphate (ATP)-Grasp and D-ala-D-ala ligase (Ddl) were found as conserved domains of vanA and vanB. We additionally found that there is notable sequence conservation, up to 66.67%, between resistomes against vancomycin and streptomycin among E. faecium. Conclusion: Resistance genes against vancomycin have highly conserved sequences between strains of Enterococcus bacteria. These conserved sequences within vanA and vanB encode for ATP-Grasp and Ddl motifs, which have functional properties for maintaining cell wall integrity. High sequence conservation is also observed among resistance genes against penicillin and streptomycin, which can inform future drug targets for broader spectrum therapies.

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Section: Discussionmentioning

confidence: 99%

Evolutionary conservation of motifs within vanA and vanB of vancomycin-resistant enterococci

et al. 2022

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“…For thiourea compounds, it is feasible to develop new Ddl inhibitors by changing the thiourea linker between the two aromatic rings (Ameryckx et al., 2020). By replacing the benzoylthiosemicarbazide linker with other linkers containing thiourea, more effective Ddl inhibitors can be obtained, such as compounds 62 and 63 , with IC 50 values of 1.48 and 0.81 μM, respectively, against the E. coli Ddl.…”

Section: Ddl Inhibitorsmentioning

confidence: 99%

Discovery of novel antibacterial agents: Recent developments in D‐alanyl‐D‐alanine ligase inhibitors

Qin

Teng

et al. 2021

Chem Biol Drug Des

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Bacterial infections can cause serious problems that threaten public health over a long period of time. Moreover, the continuous emergence of drug‐resistant bacteria necessitates the development of novel antibacterial agents. D‐alanyl‐D‐alanine ligase (Ddl) is an indispensable adenosine triphosphate‐dependent bacterial enzyme involved in the biosynthesis of peptidoglycan precursor, which catalyzes the ligation of two D‐alanine molecules into one D‐alanyl‐D‐alanine dipeptide. This dipeptide is an essential component of the intracellular peptidoglycan precursor, uridine diphospho‐N‐acetylmuramic acid (UDP‐MurNAc)‐pentapeptide, that maintains the integrity of the bacterial cell wall by cross‐linking the peptidoglycan chain, and is crucial for the survival of pathogens. Consequently, Ddl is expected to be a promising target for the development of antibacterial agents. In this review, we present a brief introduction regarding the structure and function of Ddl, as well as an overview of the various Ddl inhibitors currently being used as antibacterial agents, specifically highlighting their inhibitory activities, structure–activity relationships and mechanisms of action.

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“…The final 1,3-disubstituted thioureas 1-12 were synthesized in a single-step reaction of 3-(trifluoromethyl)aniline with various isothiocyanates, belonging to a group of dihalogenophenyl (1-4), halogenomethylphenyl (5, 6), alkylphenyl (12), or monophenylsubstituted (7)(8)(9)(10)(11) derivatives (Scheme 1). The presented selection of the phenyl ring terminal groups allowed an investigation of the impact of the substitution isomerism, as well as the influence of the electron-withdrawing elements attached to the benzene ring on the biological properties within the tested thiourea series.…”

Section: Chemistrymentioning

confidence: 99%

“…The synthesis of compounds 1, 2, 10, and 12 was described previously. The structures of the newly synthesized derivative (3)(4)(5)(6)(7)(8)11) were characterized by both 1 H and 13 C NMR spectroscopy and HRMS analysis Scheme 1. Synthetic procedure for 3-(trifluoromethyl)phenylthiourea derivatives 1-12.…”

Section: Chemistrymentioning

confidence: 99%

“…The (thio)urea branch is an element of several medicines with anticancer profiles, such as sorafenib, multikinase-inhibitory diarylthiorea derivative, or tenovin-1, the benzylthiourea, which acts as a reversible inhibitor of class III HDAC sirtuins (Figure 1). On the other hand, it was reported that (hetero)aryl terminal fragments of thiourea moiety, enriched with electron-negative substituents, could provide biological responses, not only cytotoxic [2][3][4], but also antibacterial [2][3][4][5][6][7][8], antiviral [2,[9][10][11][12], antimycobacterial [5,13], antioxidant [14], and anti-inflammatory [6] properties, as well as central nervous system activation [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives

et al. 2021

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Substituted thiourea derivatives possess confirmed cytotoxic activity towards cancer but also normal cells. To develop new selective antitumor agents, a series of 3-(trifluoromethyl)phenylthiourea analogs were synthesized, and their cytotoxicity was evaluated in vitro against the cell line panel. Compounds 1–5, 8, and 9 were highly cytotoxic against human colon (SW480, SW620) and prostate (PC3) cancer cells, and leukemia K-562 cell lines (IC50 ≤ 10 µM), with favorable selectivity over normal HaCaT cells. The derivatives exerted better growth inhibitory profiles towards selected tumor cells than the reference cisplatin. Compounds incorporating 3,4-dichloro- (2) and 4-CF3-phenyl (8) substituents displayed the highest activity (IC50 from 1.5 to 8.9 µM). The mechanisms of cytotoxic action of the most effective thioureas 1–3, 8, and 9 were studied, including the trypan blue exclusion test of cell viability, interleukin-6, and apoptosis assessments. Compounds reduced all cancerous cell numbers (especially SW480 and SW620) by 20–93%. Derivatives 2 and 8 diminished the viability of SW620 cells by 45–58%. Thioureas 1, 2, and 8 exerted strong pro-apoptotic activity. Compound 2 induced late apoptosis in both colon cancer cell lines (95–99%) and in K-562 cells (73%). All derivatives acted as inhibitors of IL-6 levels in both SW480 and SW620 cells, decreasing its secretion by 23–63%.

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Pharmacomodulations of the benzoyl-thiosemicarbazide scaffold reveal antimicrobial agents targeting d-alanyl-d-alanine ligase in bacterio

Cited by 25 publications

References 69 publications

Evolutionary conservation of motifs within vanA and vanB of vancomycin-resistant enterococci

Evolutionary conservation of motifs within vanA and vanB of vancomycin-resistant enterococci

Discovery of novel antibacterial agents: Recent developments in D‐alanyl‐D‐alanine ligase inhibitors

Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives

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