Phenanthrene Antibiotic Targets Bacterial Membranes and Kills Staphylococcus aureus With a Low Propensity for Resistance Development

Chen, Bo-Chen; Lin, Chang-Xin; Chen, Ni-Pi; Gao, Chengxian; Zhao, Ying-Jie

doi:10.3389/fmicb.2018.01593

Cited by 23 publications

(16 citation statements)

References 47 publications

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“…Nucleoside analogs have reportedly shown to disrupt membrane function and possess an inhibitory activity for biosynthetic processes including peptidoglycan, cell wall, nucleic acids, folate, and proteins 14 . We hypothesized that ticagrelor might act on the membrane of the bacterium comparable to the known membrane disruptors including nisin and polymyxin B, which have shown to dissipate membrane poteintial 15,17 -as the killing kinetics was comparable to both membrane disruptors 16,17 and the bacteriolytic activity was clearly demonstrated ( Figs. 2a and 6).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Unless otherwise stated, all agents were dissolved in DMSO and then diluted to ensure a final DMSO concentration of ≤3.2% (vol/vol). S. aureus ATCC 25923, S. aureus ATCC 29213, S. aureus ATCC 43300, and B. subtilis 168 ( Chen et al, 2018 ) were used in this study.…”

Section: Methodsmentioning

confidence: 99%

New Insights Into the Antibacterial Mechanism of Cryptotanshinone, a Representative Diterpenoid Quinone From Salvia miltiorrhiza Bunge

et al. 2021

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The rapid rise of antibiotic resistance causes an urgent need for new antimicrobial agents with unique and different mechanisms of action. The respiratory chain is one such target involved in the redox balance and energy metabolism. As a natural quinone compound isolated from the root of Salvia miltiorrhiza Bunge, cryptotanshinone (CT) has been previously demonstrated against a wide range of Gram-positive bacteria including multidrug-resistant pathogens. Although superoxide radicals induced by CT are proposed to play an important role in the antibacterial effect of this agent, its mechanism of action is still unclear. In this study, we have shown that CT is a bacteriostatic agent rather than a bactericidal agent. Metabolome analysis suggested that CT might act as an antibacterial agent targeting the cell membrane. CT did not cause severe damage to the bacterial membrane but rapidly dissipated membrane potential, implying that this compound could be a respiratory chain inhibitor. Oxygen consumption analysis in staphylococcal membrane vesicles implied that CT acted as respiratory chain inhibitor probably by targeting type II NADH:quinone dehydrogenase (NDH-2). Molecular docking study suggested that the compound would competitively inhibit the binding of quinone to NDH-2. Consistent with the hypothesis, the antimicrobial activity of CT was blocked by menaquinone, and the combination of CT with thioridazine but not 2-n-heptyl-4-hydroxyquinoline-N-oxide exerted synergistic activity against Staphylococcus aureus. Additionally, combinations of CT with other inhibitors targeting different components of the bacterial respiratory chain exhibit potent synergistic activities against S. aureus, suggesting a promising role in combination therapies.

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“…According to the earliest pharmacopeia of TCM, Shennong’s Materia Medica Classic , Chinese scholars were the first to describe the morphologic features and medicinal value of B. striata (Hossain, 2011; Chen et al, 2018). Other Chinese pharmacopeias have recorded the effect of its astringency upon hemostasis and analgesia, as well as its use for treating traumatic bleeding, ulcers, and swelling and chapped skin (He et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Chemical Constituents, Pharmacologic Properties, and Clinical Applications of Bletilla striata

Pan

Chen

2019

Front. Pharmacol.

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Bletilla striata is a plant from the Orchidaceae family that has been employed as a traditional Chinese medicine (TCM) for thousands of years in China. Here, we briefly review the published studies of the last 30 years that were related to chemical constituents, pharmacologic activities, and clinical applications of B. striata. Approximately 158 compounds have been extracted from B. striata tubers with clarified molecular structures that were classified as glucosides, bibenzyls, phenanthrenes, quinones, biphenanthrenes, dihydrophenanthrenes, anthocyanins, steroids, triterpenoids, and phenolic acids. These chemicals support the pharmacological properties of hemostasis and wound healing, and also exhibit anti-oxidation, anti-cancer, anti-viral, and anti-bacterial activities. Additionally, various clinical trials conducted on B. striata have demonstrated its marked activities as an embolizing and mucosa-protective agent, and its application for use in novel biomaterials, quality control, and toxicology. It also has been widely used as a constituent of many preparations in TCM formulations, but because there are insufficient studies on its clinical properties, its efficacy and safety cannot be established from a scientific point of view. We hope that this review will provide reference for further research and development of this unique plant.

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Phenanthrene Antibiotic Targets Bacterial Membranes and Kills Staphylococcus aureus With a Low Propensity for Resistance Development

Cited by 23 publications

References 47 publications

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

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

New Insights Into the Antibacterial Mechanism of Cryptotanshinone, a Representative Diterpenoid Quinone From Salvia miltiorrhiza Bunge

Chemical Constituents, Pharmacologic Properties, and Clinical Applications of Bletilla striata

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