Dataset Information

Bis-Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile.

ABSTRACT: Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C.?difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infection in the USA. To combat this pathogen, a new structural class of pseudo-peptides that exhibit antimicrobial activities could play an important role. Herein we report a set of bis-cyclic guanidine compounds that show potent antibacterial activity against C.?difficile with decent selectivity. Eight compounds showed high in vitro potency against C.?difficile UK6 with MIC values of 1.0??g?mL-1 , and cytotoxic selectivity index (SI) values up to 37. Moreover, the most selective compound is also effective in the treatment of C.?difficile-induced disease in a mouse model of CDI, and appears to be a very promising new candidate for the treatment of CDI.

SUBMITTER: Li C

PROVIDER: S-EPMC6121702 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Bis-Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile.

Li Chunhui C Teng Peng P Peng Zhong Z Sang Peng P Sun Xingmin X Cai Jianfeng J

ChemMedChem 20180614 14

Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C. difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infection in the USA. To combat this pathogen, a new structural class of pseudo-peptides that exhibit antimicrobial activities could play an important role. Herein we report a ...[more]

PMID: 29768720

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Project description:Clostridium difficile (C. difficile) is a Gram-positive, spore-forming, toxin-producing anaerobe that can cause nosocomial antibiotic-associated intestinal disease. Autolysin is a lytic enzyme that hydrolyzes peptidoglycans of the bacterial cell wall, with a catalytic domain and cell wall-binding domains, proven to be involved in bacterial cell wall remodeling and cell division. Although autolysins in C. difficile have been reported, the autolysins have failed to yield impressive results when used as exogenous lytic agents. In this study, we expressed and characterized the binding domains (Cwp19-BD and Acd-BD) and catalytic domains (Cwp19-CD, Acd-CD, and Cwl-CD) of C. difficile autolysins, and the domains with the best binding specificity and lytic activity were selected towards C. difficile to design a novel lytic protein Cwl-CWB2. Cwl-CWB2 showed good biosafety with significantly low hemolysis and without cytotoxicity. The results of fluorescence analysis and lytic assay demonstrated that Cwl-CWB2 has higher binding specificity and stronger lytic activity with a minimum inhibitory concentration at 13.39 ± 5.80 μg/mL against living C. difficile cells, which is significantly stronger than commercial lysozyme (3333.33 ± 1443.37 μg/mL) and other reported C. difficile autolysins. Besides, Cwl-CWB2 exhibited good stability as about 75% of the lytic activity was still retained when incubated at 37 °C for 96 h, which is considered to be a potential antimicrobial agent to combat C. difficile. KEY POINTS: • Several binding domains and catalytic domains, deriving from several Clostridium difficile autolysins, were expressed, purified, and functionally characterized. • A novel C. difficile lytic protein Cwl-CWB2 was designed from C. difficile autolysins. • The binding specificity and lytic activity of Cwl-CWB2 against C. difficile showed advantages compared with other reported C. difficile autolysins. • Cwl-CWB2 exhibited significantly low hemolysis and cytotoxicity against normal-derived colon mucosa 460 cell.

Dataset Information

Bis-Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile.

Publications

Bis-Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile.

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