Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to <i>Clostridium difficile</i> Spore Germination

Stoltz, Kristen L.; Erickson, Raymond; Staley, Christopher; Weingarden, Alexa R.; Romens, Erin; Steer, Clifford J.; Khoruts, Alexander; Sadowsky, Michael J.; Dosa, Peter I.

doi:10.1021/acs.jmedchem.7b00295

Cited by 43 publications

(38 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The values were normalized and plotted against time. From this data, the maximum rates of DPA release were determined and used to calculate the EC 50 using the Michaelis-Menten equation, as described previously [15, 16, 26, 27, 31–38]. Indeed, we observed a hierarchical order of amino acids that can stimulate germination in combination with TA (Table 1).…”

Section: Resultsmentioning

confidence: 97%

Hierarchical recognition of amino acid co-germinants during Clostridioides difficile spore germination

Shrestha

Sorg

2018

Anaerobe

View full text Add to dashboard Cite

Bile acids are an important signal for germination of Clostridioides difficile spores; however, the bile acid signal alone is not sufficient. Amino acids, such as glycine, are another signal necessary for germination by C. difficile spores. Prior studies on the amino acid signal required for germination have shown that there is a preference for the amino acid used as a signal for germination. Previously we found that d-alanine can function as a co-germinant for C. difficile spores at 37 °C but not at 25 °C. Here, we tested the ability of other amino acids to act as co-germinants with taurocholate (TA) at 37 °C and found that many amino acids previously categorized as non-co-germinants are co-germinants at 37 °C. Based on the EC values calculated for two different strains, we found that C. difficile spores recognize different amino acids with varying efficiencies. Using this data, we ranked the amino acids based on their effect on germination and found that in addition to d-alanine, other D-forms of amino acids are also used by C. difficile spores as co-germinants. Among the different types of amino acids, ones with branched chains such as valine, leucine, and isoleucine are the poorest co-germinants. However, glycine is still the most effective amino acid signal for both strains. Our results suggest that the yet-to-be-identified amino acid germinant receptor is highly promiscuous.

show abstract

Section: Resultsmentioning

confidence: 97%

Hierarchical recognition of amino acid co-germinants during Clostridioides difficile spore germination

Shrestha

Sorg

2018

Anaerobe

View full text Add to dashboard Cite

show abstract

“…28,29 The use of modified bile salts as inhibitors of spore germination has been utilized by others, and in at least one case, it was shown that a bile salt could also be used to treat C. difficile ileal pouchitis in a human. 30,86 …”

Section: Introductionmentioning

confidence: 99%

The Design, Synthesis, and Characterizations of Spore Germination Inhibitors Effective against an Epidemic Strain of Clostridium difficile

Sharma

Yip

Esposito³

et al. 2018

J. Med. Chem.

View full text Add to dashboard Cite

Clostridium difficile infections (CDI), particularly those caused by the BI/NAP1/027 epidemic strains, are challenging to treat. One method to address this disease is to prevent the development of CDI by inhibiting the germination of C. difficile spores. Previous studies have identified cholic amide m-sulfonic acid, CamSA, as an inhibitor of spore germination. However, CamSA is inactive against the hypervirulent strain R20291. To circumvent this problem, a series of cholic acid amides were synthesized and tested against R20291. The best compound in the series was the simple phenyl amide analogue which possessed an IC50 value of 1.8 μM, more than 225 times as potent as the natural germination inhibitor, chenodeoxycholate. This is the most potent inhibitor of C. difficile spore germination described to date. QSAR and molecular modeling analysis demonstrated that increases in hydrophobicity and decreases in partial charge or polar surface area were correlated with increases in potency.

show abstract

“…28,29 However, germination acti-vators and inhibitors do not neatly segregate into cholateand chenodeoxycholate-derivatives, respectively. 22,28,30 Bile Acids Can Be Toxic to C. difficile Vegetative Cell Growth Both cholate and chenodeoxycholate are produced in the liver as the end products of cholesterol metabolism. These bile acids can also be conjugated to the amino acids, glycine, or taurine, in the liver; this modification lowers their pK a so that they can be termed bile salts.…”

Section: The Spore Form Of C Difficile Is Its Major Infectious Particlementioning

confidence: 99%

Clostridioides difficile Spores: Bile Acid Sensors and Trojan Horses of Transmission

Shen

2020

Clinics in Colon and Rectal Surgery

View full text Add to dashboard Cite

The Gram-positive, spore-forming bacterium, Clostridioides difficile is the leading cause of healthcare-associated infections in the United States, although it also causes a significant number of community-acquired infections. C. difficile infections, which range in severity from mild diarrhea to toxic megacolon, cost more to treat than matched infections, with an annual treatment cost of approximately $6 billion for almost half-a-million infections. These high–treatment costs are due to the high rates of C. difficile disease recurrence (>20%) and necessity for special disinfection measures. These complications arise in part because C. difficile makes metabolically dormant spores, which are the major infectious particle of this obligate anaerobe. These seemingly inanimate life forms are inert to antibiotics, resistant to commonly used disinfectants, readily disseminated, and capable of surviving in the environment for a long period of time. However, upon sensing specific bile salts in the vertebrate gut, C. difficile spores transform back into the vegetative cells that are responsible for causing disease. This review discusses how spores are ideal vectors for disease transmission and how antibiotics modulate this process. We also describe the resistance properties of spores and how they create challenges eradicating spores, as well as promote their spread. Lastly, environmental reservoirs of C. difficile spores and strategies for destroying them particularly in health care environments will be discussed.

show abstract

Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination

Cited by 43 publications

References 50 publications

Hierarchical recognition of amino acid co-germinants during Clostridioides difficile spore germination

Hierarchical recognition of amino acid co-germinants during Clostridioides difficile spore germination

The Design, Synthesis, and Characterizations of Spore Germination Inhibitors Effective against an Epidemic Strain of Clostridium difficile

Clostridioides difficile Spores: Bile Acid Sensors and Trojan Horses of Transmission

Contact Info

Product

Resources

About