Novel FR-900493 Analogues That Inhibit the Outgrowth of <i>Clostridium difficile</i> Spores

Mitachi, Katsuhiko; Yun, Hyun Gi; Kurosu, Sara M.; Eslamimehr, Shakiba; Lemieux, Maddie R.; Klaić, Lada; Clemons, William M.; Kurosu, Masaaki

doi:10.1021/acsomega.7b01740

Cited by 20 publications

(17 citation statements)

References 49 publications

(125 reference statements)

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“…The percentage of hemolysis was calculated from the equation (100 × (A sample −A negative control ) / (A positive control – A negative control )). 41 …”

Section: Methodsmentioning

confidence: 99%

An antimycobacterial pleuromutilin analogue effective against dormant bacilli

Lemieux

Siricilla

Mitachi

et al. 2018

Bioorganic & Medicinal Chemistry

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Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (1) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2xMIC concentrations. Pharmacokinetic studies indicate that 1 has an oral bioavailability with an average F-value of 27.6%. Pleuromutilin may have the potential to be developed into an orally administered anti-TB drug.

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“…The percentage of hemolysis was calculated from the equation (100 × (A sample −A negative control ) / (A positive control – A negative control )). 41 …”

Section: Methodsmentioning

confidence: 99%

An antimycobacterial pleuromutilin analogue effective against dormant bacilli

Lemieux

Siricilla

Mitachi

et al. 2018

Bioorganic & Medicinal Chemistry

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“…Although C. difficile spore is naturally resistant to most antibiotics including vancomycin and metronidazole 24,25 , however, in this study, we found that ticagrelor inhibited spore germination in a dose-dependent manner. It has been shown that nucleoside antibiotic derivatives inhibit the outgrowth of C. difficile spores at the concentration of 2X MIC 26 . It is possible that nucleoside analogs may compete with the nucleosides required as germinants for C. difficile spores 27 .…”

Section: Scientific Reports |mentioning

confidence: 99%

Repurposing a platelet aggregation inhibitor ticagrelor as an antimicrobial against Clostridioides difficile

Phanchana

Phetruen

Harnvoravongchai

et al. 2020

Sci Rep

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Drug resistance in Clostridioides difficile becomes a public health concern worldwide, especially as the hypervirulent strains show decreased susceptibility to the first-line antibiotics for C. difficile treatment. Therefore, the simultaneous discovery and development of new compounds to fight this pathogen are urgently needed. in order to determinate new drugs active against C. difficile, we identified ticagrelor, utilized for the prevention of thrombotic events, as exhibiting potent growth-inhibitory activity against C. difficile. Whole-cell growth inhibition assays were performed and compared to vancomycin and metronidazole, followed by determining time-kill kinetics against C. difficile. Activities against biofilm formation and spore germination were also evaluated. Leakage analyses and electron microscopy were applied to confirm the disruption of membrane structure. Finally, ticagrelor's ability to synergize with vancomycin and metronidazole was determined using checkerboard assays. our data showed that ticagrelor exerted activity with a MIC range of 20-40 µg/mL against C. difficile. this compound also exhibited an inhibitory effect on biofilm formation and spore germination. Additionally, ticagrelor did not interact with vancomycin nor metronidazole. Our findings revealed for the first time that ticagrelor could be further developed as a new antimicrobial agent for fighting against C. difficile.A Gram-positive, spore-forming bacterium Clostridioides difficile, formerly known as Clostridium difficile is currently one of the most concerning nosocomial pathogens 1 . C. difficile tops the list of nosocomial infections with the annual estimation of more than 200,000 cases and $1 billion healthcare costs in the United States alone 2 . It has been postulated that C. difficile infection (CDI) in humans may come from animals as an overlap between human and animal isolates has been observed 3 . Patients with CDI can appear asymptomatic, however, the excessive use of antibiotics can cause an alteration in indigenous gut microbiota, enabling C. difficile to populate, produce toxins and become pathogenic, thereby causing severe diarrhoea, pseudomembranous colitis and occasionally fatality, especially in patients aged more than 65 4 . The treatment for CDI is currently limited to vancomycin, metronidazole, and fidaxomicin 5 , however, increase in treatment failures CDI due to recurrence has rendered these antibiotics ineffective 6 . Although metronidazole was initially used as the first-line agent for treatment of non-severe CDI cases and vancomycin was a drug of choice for more severe and recurrent CDI 4 , however, recent guidelines from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) suggests that either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI, unless in the setting where access to these drugs are limited 5-7 . Emergence of resistant strains to these antibiotics has been demonstrated, causing reduction in t...

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“…The monomethoxytetrachlorodiphenylmethoxymethyl (MTPM)-protected uridine 2 was prepared according to the previously reported procedure [1]. The primary alcohol of 2 was oxidized by a modified Swern condition to provide the corresponding aldehyde in quantitative yield, which was then subjected to Carreira’s asymmetric alkynation reaction using (−)- N -methylephedrine [2], yielding the ( S )-propargyl alcohol 3 in 80% yield with selectivity of >98:2. NIS-AgBF 4 promoted ribosylation of ( S )-propargyl alcohol 3 with 4 furnished the β-riboside 5 exclusively in 95% yield.…”

Section: Description Of Protocolmentioning

confidence: 99%