In Vitro
 Activities of MCB3681 and Eight Comparators against Clostridium difficile Isolates with Known Ribotypes and Diverse Geographical Spread

Freeman, Joseph T.; Pilling, Sally; Vernon, Jon J; Wilcox, Mark H.

doi:10.1128/aac.02077-16

Cited by 12 publications

(7 citation statements)

References 10 publications

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“…Freeman et al 41 studied the in vitro activity of MCB3681 and 8 comparator agents against 199 prevalent or emerging European C. difficile RTs isolated between 2011 and 2013 using a Wilkens-Chalgren agar dilution method. MCB3681 was active against all isolates, including RTs 027, 001, 017,018, and 356; there was an MIC 90 of 0.25 µg/mL (range, 0.008-0.5 μg/mL) and a geometric mean MIC of 0.12 μg/mL.…”

Section: Dnv3837 (Mcb3681/mcb3687)mentioning

confidence: 99%

Investigational Treatment Agents for Recurrent Clostridioides difficile Infection (rCDI)

Kullar¹,

Tran²,

Goldstein³

2020

JEP

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Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea that is deemed a global health threat. C. difficile strain BI/NAP1/027 has contributed to the increase in the mortality, severity of CDI outbreaks and recurrence rates (rCDI). Updated CDI treatment guidelines suggest vancomycin and fidaxomicin as initial first-line therapies that have initial clinical cure rates of over 80%. Unacceptably high recurrence rates of 15-30% in patients for the first episode and 40% for the second recurrent episode are reported. Alternative treatments for rCDI include fecal microbiota transplant and a human monoclonal antibody, bezlotoxumab, that can be used in patients with high risk of rCDI. Various emerging potential therapies with narrow spectrum of activity and little systemic absorption that are in development include 1) Ibezapolstat (formerly ACX-362E), MGB-BP-3, and DS-2969b-targeting bacterial DNA replication, 2) CRS3213 (REP3123)-inhibiting toxin production and spore formation, 3) ramizol and ramoplanin-affecting bacterial cell wall, 4) LFF-571-blocking protein synthesis, 5) Alanyl-L-Glutamine (alanylglutamine)inhibiting damage caused by C. difficile by protecting intestinal mucosa, and 6) DNV3837 (MCB3681)-prodrug consisting of an oxazolidinone-quinolone combination that converts to the active form DNV3681 that has activity in vitro against C. difficile. This review article provides an overview of these developing drugs that can have potential role in the treatment of rCDI and in lowering recurrence rates.

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Section: Dnv3837 (Mcb3681/mcb3687)mentioning

confidence: 99%

Investigational Treatment Agents for Recurrent Clostridioides difficile Infection (rCDI)

Kullar¹,

Tran²,

Goldstein³

2020

JEP

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“…[48] In the last few years, atom-and step-economical CÀ N bond formation via CÀ H activation has been explored extensively for the newer drug candidates. Wang et al, developed an efficient synthetic methodology for the synthesis of 4-quinolones (27) via CÀ H amidation of enaminone catalyzed by cobalt(III) and rhodium(III). The required amidated intermediates (26) were synthesized under the optimized reaction conditions by coupling between enaminone (24) and dioxazolone (25) followed by subsequent hydrolysis-cyclization reaction in the presence of aq.…”

Section: Metal Assisted Synthesis Of 4-quinolonesmentioning

confidence: 99%

“…[14][15] In addition to the above, now they are widely explored as anti-HIV, [16] antimalarial agents, [17,18] alkaline phosphatase inhibitors, [19] antifilarial agents, [20] and antidiabetic agent, [21] for the development of novel therapeutic agents. Different drugs containing quinolone nucleus such as caderofloxacin lactate, [22] DX-619, [23] 259 C, [24] GSK945237, [25] MCB3681, [26][27] WCK-1152, [28] nemonoxacin, delafloxacin" [29][30] voreloxin, [31] (figure 2), etc. are under different phases of clinical trials for various activities such as antibacterial activity, topoisomerase inhibitory activity, DNA gyrase inhibitory activity, community-acquired pneumonia, etc.…”

Section: Introductionmentioning

confidence: 99%

Recent Developments in the Synthetic Strategies of 4‐Quinolones and Its Derivatives

2020

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The ubiquitous presence of 4-quinolones and its derivatives in a wide range of natural as well as synthetic drug molecules made them molecule of utmost importance for organic and medicinal chemists. Their wide array of biological activities such as antimicrobial, anticancer, anti-HIV, genitourinary infection, antifilarial, etc., has augmented their appeal both for synthetic and medicinal chemistry campaigns. Moreover, they are valuable intermediates for the synthesis of various fused heterocyclic compounds of synthetic and medicinal importance. Considering their array of synthetic and biological importance, new strategies for the synthesis of 4-quinolones and their derivatives have been designed and successfully demonstrated by researchers around the globe. The present review covers recent advances in the synthetic chemistry of 4quinolones since 2015 along with an insight into their mechanistic studies. We hope that the review article will serve as a valuable tool for the scientific community engaged in the synthesis and utilization of 4-quinolones and their derivatives.

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“…MCB3681 is a hybrid fluoroquinolone‐oxazolidinone produced by Morphochem that has a water‐soluble prodrug formulation termed MCB3837 that can be given by IV, making this therapy an option for severe and complicated C. difficile infections when oral therapy fails. It has been shown to have activity against Gram‐positive bacteria, including C. difficile , but limited activity against Gram‐negative bacteria such as those native to the human gut . A phase I study where 12 healthy volunteers were given daily intravenous infusions of 6 mg/kg MCB3837 over 12 h for 5 days showed little impact on microbiota and suggested the drug was well tolerated .…”

Section: Areas For Improvement and Targets For Emerging Therapiesmentioning

confidence: 99%

“…It has been shown to have activity against Gram-positive bacteria, including C. difficile, but limited activity against Gram-negative bacteria such as those native to the human gut. [78][79][80] A phase I study where 12 healthy volunteers were given daily intravenous infusions of 6 mg/kg MCB3837 over 12 h for 5 days showed little impact on microbiota and suggested the drug was well tolerated. 81 Phase II/III trials are being planned currently, and the U.S. Food and Drug Administration (FDA) designated MCB3837 as a Qualified Infectious Disease Product for the treatment of CDI.…”

Section: Treatment Of Primary Cdi: Reducing Severity and Increasing Cmentioning

confidence: 99%

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

Dieterle

Rao

Young

2018

Annals of the New York Academy of Sciences

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Clostridium difficile is the leading infectious cause of antibiotic-associated diarrhea and colitis. Clostridium difficile infection (CDI) places a heavy burden on the health care system, with nearly half a million infections yearly and an approximate 20% recurrence risk after successful initial therapy. The high incidence has driven new research on improved prevention such as the emerging use of probiotics, intestinal microbiome manipulation during antibiotic therapies, vaccinations, and newer antibiotics that reduce the disruption of the intestinal microbiome. While the treatment of acute C. difficile is effective in most patients, it can be further optimized by adjuvant therapies that improve the initial treatment success and decrease the risk of subsequent recurrence. Lastly, the high risk of recurrence has led to multiple emerging therapies that target toxin activity, recovery of the intestinal microbial community, and elimination of latent C. difficile in the intestine. In summary, CDIs illustrate the complex interaction among host physiology, microbial community, and pathogen that requires specific therapies to address each of the factors leading to primary infection and recurrence.

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In Vitro Activities of MCB3681 and Eight Comparators against Clostridium difficile Isolates with Known Ribotypes and Diverse Geographical Spread

Cited by 12 publications

References 10 publications

<p>Investigational Treatment Agents for Recurrent <em>Clostridioides difficile</em> Infection (rCDI)</p>

<p>Investigational Treatment Agents for Recurrent <em>Clostridioides difficile</em> Infection (rCDI)</p>

Recent Developments in the Synthetic Strategies of 4‐Quinolones and Its Derivatives

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

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