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

Sharma, Shiv K.; Yip, Cecil C.; Esposito, Emilio Xavier; Sharma, Prateek; Simon, Matthew P.; Abel-Santos, Ernesto; Firestine, Steven M.

doi:10.1021/acs.jmedchem.8b00632

Cited by 18 publications

(24 citation statements)

References 84 publications

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“…The observation that specific bile acids can potently inhibit C. difficile spore germination, combined with the finding that C. difficile germination mutants are impaired in their ability to colonize hamsters and cause disease [17][18][19] and have led to the proposal that bile salt analogs could be used to prevent C. difficile-associated disease. Consistent with this hypothesis, synthetic bile acid analogs have been developed that prevent C. difficile spore germination both in vitro 28,30,49 and during infection of mice, 50 suggesting that these antigermination agents could be developed for clinical use. Indeed, even subinhibitory doses of these agents reduce disease severity.…”

Section: Antigermination Strategies For Preventing C Difficile Infecmentioning

confidence: 94%

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

Shen

2020

Clinics in Colon and Rectal Surgery

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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.

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Section: Antigermination Strategies For Preventing C Difficile Infecmentioning

confidence: 94%

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

Shen

2020

Clinics in Colon and Rectal Surgery

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“…Administration of CamSA severely diminished the amount of recoverable CD vegetative cells in a dose-dependent manner. Importantly, CamSA was not effective against all strains of CD, in particular the outbreak-associated strain R20291 99 belonging to the RT027 ribotype. However, a phenyl amide analogue of CamSA was synthesized and demonstrated to be 225 times more potent at inhibiting R20291 CD spore germination compared to CDCA.…”

Section: Small Molecule Inhibitors Of C Difficile Toxinsmentioning

confidence: 95%

“…However, a phenyl amide analogue of CamSA was synthesized and demonstrated to be 225 times more potent at inhibiting R20291 CD spore germination compared to CDCA. 99 …”

Section: Small Molecule Inhibitors Of C Difficile Toxinsmentioning

confidence: 99%

Anti-virulence strategies for Clostridioides difficile infection: advances and roadblocks

2020

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Clostridioides difficile infection (CDI) is a common healthcare- and antibiotic-associated diarrheal disease. If mis-diagnosed, or incompletely treated, CDI can have serious, indeed fatal, consequences. The clinical and economic burden imposed by CDI is great, and the US Centers for Disease Control and Prevention has named the causative agent, C. difficile (CD), as an Urgent Threat To US healthcare. CDI is also a significant problem in the agriculture industry. Currently, there are no FDA-approved preventives for this disease, and the only approved treatments for both human and veterinary CDI involve antibiotic use, which, ironically, is associated with disease relapse and the threat of burgeoning antibiotic resistance. Research efforts in multiple laboratories have demonstrated that non-toxin factors also play key roles in CDI, and that these are critical for disease. Specifically, key CD adhesins, as well as other surface-displayed factors have been shown to be major contributors to host cell attachment, and as such, represent attractive targets for anti-CD interventions. However, research on anti-virulence approaches has been more limited, primarily due to the lack of genetic tools, and an as-yet nascent (but increasingly growing) appreciation of immunological impacts on CDI. The focus of this review is the conceptualization and development of specific anti-virulence strategies to combat CDI. Multiple laboratories are focused on this effort, and the field is now at an exciting stage with numerous products in development. Herein, however, we focus only on select technologies (Figure 1) that have advanced near, or beyond, pre-clinical testing (not those that are currently in clinical trial), and discuss roadblocks associated with their development and implementation.

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“…Our previous work showed that a combination between cholic acid and heterocyclic scaffolds improved the antibacterial property ( Figure 1 ) [ 21 ]. In 2018, Sharma et al presented a new pyridinyl-substituted cholic acid analogue that was effective against an epidemic strain of Clostridium difficile ( Figure 1 ) [ 22 ]. Recently, Chuchkov et al prepared a hybrid structure between heterocycle penciclovir and cholic acid, and the product showed antiviral activity ( Figure 1 ) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

Rasras¹,

El‐Naggar²,

Safwat³

et al. 2022

Beilstein J. Org. Chem.

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A new chemical library based on the hybridization of cholic acid with the heterocyclic moiety 1,3,4-oxadizole was synthesized, and tested for antimicrobial activity against Gram-positive, Gram-negative bacteria, and fungi. Among the synthesized compounds, the most potent derivatives against S. aureus were 4t, 4i, 4p, and 4c with MIC values between 31 and 70 µg/mL, while compound 4p was the most active one against Bacillus subtilis with a MIC value of 70 µg/mL. Interestingly, compounds 4a and 4u exerted selective activity against Gram-positive bacteria. The synthesized compounds showed good activity against A. fumigatus and C. albicans and compound 4v exhibited selective activity against fungi only.

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

Cited by 18 publications

References 84 publications

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

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

Anti-virulence strategies for Clostridioides difficile infection: advances and roadblocks

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

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