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Progress in the discovery of treatments for C. difficile infection: A clinical and medicinal chemistry review.

Tsutsumi LS, Owusu YB, Hurdle JG, Sun D - Curr Top Med Chem (2014)

Bottom Line: Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality.Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments.This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA. dianqing@hawaii.edu.

ABSTRACT
Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.

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Chemical structures of synthetic small molecule anti-difficile agents.
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Figure 4: Chemical structures of synthetic small molecule anti-difficile agents.

Mentions: Small molecules that are totally synthetic are the second component of the current antibiotic repository. One such example, the synthetic fluoroquinolones are a class of highly effective and broad spectrum antibiotics [236]. However, recent efforts based on high-throughput screens of novel targets identified by bacterial genomics to discover and develop new synthetic scaffolds have not yet been as successful as natural products [237, 238]. Despite this conclusion, synthetic small molecule antibiotics are still alluring to develop due to their structural simplicity and ease of production if found to be an effective therapeutic. Furthermore, advances in novel target identification and screening methodology may prove to find more active synthetic scaffolds in the future [238, 239]. The recently reported synthetic molecules found to be active against C. difficile are summarized in Fig. 4.


Progress in the discovery of treatments for C. difficile infection: A clinical and medicinal chemistry review.

Tsutsumi LS, Owusu YB, Hurdle JG, Sun D - Curr Top Med Chem (2014)

Chemical structures of synthetic small molecule anti-difficile agents.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921470&req=5

Figure 4: Chemical structures of synthetic small molecule anti-difficile agents.
Mentions: Small molecules that are totally synthetic are the second component of the current antibiotic repository. One such example, the synthetic fluoroquinolones are a class of highly effective and broad spectrum antibiotics [236]. However, recent efforts based on high-throughput screens of novel targets identified by bacterial genomics to discover and develop new synthetic scaffolds have not yet been as successful as natural products [237, 238]. Despite this conclusion, synthetic small molecule antibiotics are still alluring to develop due to their structural simplicity and ease of production if found to be an effective therapeutic. Furthermore, advances in novel target identification and screening methodology may prove to find more active synthetic scaffolds in the future [238, 239]. The recently reported synthetic molecules found to be active against C. difficile are summarized in Fig. 4.

Bottom Line: Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality.Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments.This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA. dianqing@hawaii.edu.

ABSTRACT
Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.

Show MeSH
Related in: MedlinePlus