Studies on the Importance of the 7α-, and 12α- hydroxyl groups of N-Aryl-3α,7α,12α-trihydroxy-5β-cholan-24-amides on their Antigermination Activity Against a Hypervirulent Strain of Clostridioides (Clostridium) difficile

Sharma, Shiv K.; Yip, Cecil C.; Simon, Matthew P.; Phan, Jacqueline R.; Abel-Santos, Ernesto; Firestine, Steven M.

doi:10.1016/j.bmc.2021.116503

Cited by 7 publications

(10 citation statements)

References 28 publications

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“…Chenodeoxycholic acid is a primary bile acid directly synthesized from cholesterol, and it is an inhibitor of Clostridioides difficile . 40 This is consistent with the observed increase of Clostridioides in the antibiotic treatment group. TMAO, a metabolic product of gut microbiota, is associated with an increased risk of cardiovascular diseases, diabetes, and cancer.…”

Section: Discussionsupporting

confidence: 89%

Antibiotic-induced gut microbiota dysbiosis altered host metabolism

Shi

Liu

et al. 2023

Mol. Omics

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Section: Discussionsupporting

confidence: 89%

Antibiotic-induced gut microbiota dysbiosis altered host metabolism

Shi

Liu

et al. 2023

Mol. Omics

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“…Additional investigation revealed that the simple phenyl substitution, CaPA (3b, Figure 1) gave potent inhibition (IC50 = 1.8 µM) against a range of C. difficile strains and could prevent C. difficile infections in mouse and hamster models 15,21 . We have further shown that the cholic acid nucleus gives the most potent inhibition of germination; however, the CDCA moiety also inhibits but with less potency 22 . Finally, other groups have explored ursodeoxycholate analogs as antigerminants 16,[25][26] Our previous studies have focused on secondary amide substitutions of cholic acid as spore germination inhibitors 15 .…”

Section: Introductionmentioning

confidence: 71%

“…Given the connection between spore germination and bile salts, we and others have shown that bile salt analogs can inhibit germination and prevent the development of C. difficile colitis 12,[15][16][17][18][19][20][21][22] . Several natural bile salts inhibit germination in vitro; however, their use to treat patients has not been successful 19 .…”

Section: Introductionmentioning

confidence: 99%

The Design, Synthesis, and Inhibition of Clostridioides difficile Spore Germination by Acyclic and Bicyclic Tertiary Amide Analogs of Cholate

Sharma

Schilke

Phan

et al. 2023

Preprint

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Clostridioides difficile infection (CDI) is a major identifiable cause of antibiotic-associated diarrhea. In our previous study (J. Med Chem, 2018, 61, 6759-6778), we have identified N-phenyl-cholan-24-amide as a potent inhibitor of spore germination. The most potent compounds in our previous work are N-arylamides. We were interested in the role that the conformation of the amide plays in activity. Previous research has shown that secondary N-arylamides exist exclusively in the coplanar trans conformation while tertiary N-methyl-N-arylamides exist in a non-planar, cis conformation. The N-methy-N-phenyl-cholan-24-amide was 17-fold less active compared to the parent compounds suggesting the importance of the orientation of the phenyl ring. To lock the phenyl ring into a trans conformation, cyclic tertiary amides were prepared. Indoline and quinoline cholan-24-amides were both inhibitors of spore germination; however, the indoline analogs were most potent. Isoindoline and isoquinoline amides were inactive. We found that the simple indoline derivative gave an IC50 value of 1 M, while the 5-fluoro-substituted compound (5d) possessed an IC50 of 400 nM. To our knowledge, 5d is the most potent known spore germination inhibitor described to date. Taken together, our results indicate that the trans, coplanar conformation of the phenyl ring is required for potent inhibition.

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“…Because of the critical nature of spore germination in the onset of infection, we expect that anti-germination therapy will prevent CDI and its relapse [23]. Given the role that bile salts play in C. difficile spore germination, we and others have examined sterane compounds as inhibitors of spore germination [11,[24][25][26][27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of germination inhibition ofClostridioides difficilespores by an aniline substituted cholate derivative (CaPA)

Yip

Abel-Santos

2023

Preprint

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Clostridioides difficile infection (CDI) is the major identifiable cause of antibiotic-associated diarrhea and has been declared an urgent threat by the CDC. C. difficile forms dormant and resistant spores that serve as infectious vehicles for CDI. To cause disease, C. difficile spores recognize taurocholate and glycine to trigger the germination process. In contrast to other sporulating bacteria, C. difficile spores are postulated to use a protease complex, CspABC, to recognize its germinants. Since spore germination is required for infection, we have developed anti-germination approaches for CDI prophylaxis. Previously, the bile salt analog CaPA (an aniline-substituted cholic acid) was shown to block spore germination and protect rodents from CDI caused by multiple C. difficile strains. In this study, we found that CaPA is an alternative substrate inhibitor of C. difficile spore germination. By competing with taurocholate for binding, CaPA delays C. difficile spore germination and reduces spore viability, thus diminishing the number of outgrowing vegetative bacteria. We hypothesize that the reduction of toxin-producing bacterial burden explains CaPAs protective activity against murine CDI. Previous data combined with our results suggests that CaPA binds tightly to C. difficile spores in a CspC-dependent manner and irreversibly trap spores in an alternative, time-delayed, and low yield germination pathway. Our results are also consistent with kinetic data suggesting the existence of at least two distinct bile salt binding sites in C. difficile spores.

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Studies on the Importance of the 7α-, and 12α- hydroxyl groups of N-Aryl-3α,7α,12α-trihydroxy-5β-cholan-24-amides on their Antigermination Activity Against a Hypervirulent Strain of Clostridioides (Clostridium) difficile

Cited by 7 publications

References 28 publications

Antibiotic-induced gut microbiota dysbiosis altered host metabolism

Antibiotic-induced gut microbiota dysbiosis altered host metabolism

The Design, Synthesis, and Inhibition of Clostridioides difficile Spore Germination by Acyclic and Bicyclic Tertiary Amide Analogs of Cholate

Mechanism of germination inhibition ofClostridioides difficilespores by an aniline substituted cholate derivative (CaPA)

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