Prospects for flavonoid and related phytochemicals as nature-inspired treatments for <i>Clostridium difficile</i>
 infection

Wu, Xiaoqian; Alam, Mohammad Zahangir; Feng, Lian‐Shun; Tsutsumi, Lissa S.; Sun, Dianqing; Hurdle, Julian G.

doi:10.1111/jam.12344

Cited by 19 publications

(27 citation statements)

References 30 publications

(54 reference statements)

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“…In 2013, the anti-difficile activity of naturally occurring flavonoid compounds was reported by Wu et al [235]. Synthetic olympicin A (Fig.…”

Section: Newer Agents For CDImentioning

confidence: 95%

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Tsutsumi¹,

Owusu²,

Hurdle³

et al. 2013

CTMC

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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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“…In 2013, the anti-difficile activity of naturally occurring flavonoid compounds was reported by Wu et al [235]. Synthetic olympicin A (Fig.…”

Section: Newer Agents For CDImentioning

confidence: 95%

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Tsutsumi¹,

Owusu²,

Hurdle³

et al. 2013

CTMC

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“… 44 , 45 Very recently, we have shown that synthetic olympicin A also exhibited good activity against Clostridium difficile (MIC = 1–2 μg/mL). 46 Inspired by the antibacterial activity of the natural products abyssinone II and olympicin A, in this work we employed the 4-chromanone and chalcone structural scaffolds as chemical starting points to design and synthesize chemically modified flavonoid analogues. Subsequently, several series of structurally related flavonoids were synthesized and evaluated in vitro against a broad set of bacterial pathogens and a detailed structure–activity relationship (SAR) has been obtained.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structure–Activity Relationship Studies, and Antibacterial Evaluation of 4-Chromanones and Chalcones, as Well as Olympicin A and Derivatives

et al. 2014

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On the basis of recently reported abyssinone II and olympicin A, a series of chemically modified flavonoid phytochemicals were synthesized and evaluated against Mycobacterium tuberculosis and a panel of Gram-positive and -negative bacterial pathogens. Some of the synthesized compounds exhibited good antibacterial activities against Gram-positive pathogens including methicillin resistant Staphylococcus aureus with minimum inhibitory concentration as low as 0.39 μg/mL. SAR analysis revealed that the 2-hydrophobic substituent and the 4-hydrogen bond donor/acceptor of the 4-chromanone scaffold together with the hydroxy groups at 5- and 7-positions enhanced antibacterial activities; the 2′,4′-dihydroxylated A ring and the lipophilic substituted B ring of chalcone derivatives were pharmacophoric elements for antibacterial activities. Mode of action studies performed on selected compounds revealed that they dissipated the bacterial membrane potential, resulting in the inhibition of macromolecular biosynthesis; further studies showed that selected compounds inhibited DNA topoisomerase IV, suggesting complex mechanisms of actions for compounds in this series.

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“…Minimum inhibitory and minimum bactericidal concentrations of compounds against C. difficile were determined as described by Wu et al (11,23). The MICs were determined using ϳ10 6 CFU/ml of inoculum of C. difficile in 24-well microtiter plates containing 2-fold serial dilutions of compounds in a total volume of 1 ml.…”

Section: Compoundsmentioning

confidence: 99%

“…Time-kill kinetics were evaluated against both the logarithmic-and stationary-phase cultures, as described by Wu et al (11,23). Logarithmicphase (OD 600 , Ϸ0.3) and stationary-phase cultures were exposed to 1, 4, and 16ϫ the MIC of the compounds.…”

Section: Compoundsmentioning

confidence: 99%

Mode of Action and Bactericidal Properties of Surotomycin against Growing and Nongrowing Clostridium difficile

Alam

Mascio

et al. 2015

Antimicrob Agents Chemother

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d Surotomycin (CB-183,315), a cyclic lipopeptide, is in phase 3 clinical development for the treatment of Clostridium difficile infection. We report here the further characterization of the in vitro mode of action of surotomycin, including its activity against growing and nongrowing C. difficile. This was assessed through time-kill kinetics, allowing a determination of the effects on the membrane potential and permeability and macromolecular synthesis in C. difficile. Against representative strains of C. difficile, surotomycin displayed concentration-dependent killing of both logarithmic-phase and stationary-phase cultures at a concentration that was <16؋ the MIC. Exposure resulted in the inhibition of macromolecular synthesis (in DNA, RNA, proteins, and cell wall). At bactericidal concentrations, surotomycin dissipated the membrane potential of C. difficile without changes to the permeability of propidium iodide. These observations are consistent with surotomycin acting as a membrane-active antibiotic, exhibiting rapid bactericidal activities against growing and nongrowing C. difficile. The Gram-positive spore-forming anaerobic bacterium Clostridium difficile is the leading cause of hospital-acquired diarrhea in North America and Europe (1, 2). Elderly hospitalized patients on broad-spectrum antibiotics are the main target population, but recent observations indicate there is an increase in the incidence of C. difficile infection (CDI) in the community without known risk factors (3, 4). In the United States in 2011, there were an estimated 500,000 cases of CDI resulting in 29,300 deaths (5), which reflects the devastating impact of CDI since the turn of the last century. Furthermore, the number of cases of severe CDI has escalated, coinciding with the emergence of epidemic ribotypes, such as BI/NAP1/027 (2, 6). BI/NAP1/027 is now responsible for a significant number of cases of hospital-acquired CDI in North America (5, 6).For Ͼ30 years, vancomycin and metronidazole have been the first-line treatment choices for CDI (7). Metronidazole is prescribed for mild to moderate CDI, while vancomycin is recommended for severe CDI (6,8). However, rates of recurrence of 20 to Ն25% in severe CDI are common following treatment with metronidazole or vancomycin (6, 9, 10). The mode of action of vancomycin is well established, involving inhibition of the later stages of peptidoglycan biosynthesis, which primarily kill rapidly growing C. difficile (11). Metronidazole undergoes biochemical reduction to form reactive species that target DNA and is potent in vitro, but only low concentrations reside in the gastrointestinal tract (12-16). Fidaxomicin, which targets the bacterial RNA polymerase inhibitor, has a narrower spectrum of activity than that of metronidazole and vancomycin and is superior in the prevention of CDI recurrence (17, 18). However, additional novel therapeutics are required to effectively treat CDI and reduce the rates of recurrence following initial therapy.Surotomycin is a minimally absorbed narrow-spectrum cycl...

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Prospects for flavonoid and related phytochemicals as nature-inspired treatments for Clostridium difficile infection

Cited by 19 publications

References 30 publications

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Synthesis, Structure–Activity Relationship Studies, and Antibacterial Evaluation of 4-Chromanones and Chalcones, as Well as Olympicin A and Derivatives

Mode of Action and Bactericidal Properties of Surotomycin against Growing and Nongrowing Clostridium difficile

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