Chemical Modulation of the Biological Activity of Reutericyclin: a Membrane-Active Antibiotic from Lactobacillusreuteri

Cherian, Philip; Wu, Xiaoqian; Maddox, Marcus M.; Singh, Anumeha; Lee, Richard; Hurdle, Julian G.

doi:10.1038/srep04721

Cited by 30 publications

(44 citation statements)

References 32 publications

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“…Against Enterococcus faecalis and methicillin-resistant S. aureus (MRSA), most hybrids had MICs >25 µg/ml. Previously, we reported that the antimicrobial activity of tetramic acids belonging to the membrane active reutericyclin class was influenced by hydrophobic substituents at the N1, C5, and 3-positions of the tetramic core and that the simple hydrophilic tetramic acid core alone did not possess measurable antibacterial activity (MICs > 200 µg/ml) against Gram-positive bacteria [18, 34]. In comparison, for tetramic acid-ampicillin hybrids, different substituents at the C5 and N1-positions on the tetramic core, irrespective of their size, shape, hydrophobicity, and polarity produced similar activity, and no clear SAR was observed.…”

Section: Resultsmentioning

confidence: 99%

“…reutericyclins) are typically inactive against the Gram-negative test panel in Table 2 [15, 18, 34]. However, against the panel of type strains of gram-negative bacteria, fusion of ampicillin with tetramic acid produced variable effects against the different species (Table 2), with a general observed trend that some hybrids showed increased activity over ampicillin and carbenicillin, but were inferior to piperacillin for some key species.…”

Section: Resultsmentioning

confidence: 99%

“…Tetramic acid motifs are found in a wide variety of pharmacologically active natural products, with many displaying antifungal and antibacterial activities [13–15]. Molecules bearing the tetramic acid core demonstrate diverse modes of action ranging from inhibition of cell wall [16] and RNA synthesis [17] and dissipation of the membrane potential [18]. The tetramic acid motif has the ability to interact with acid and metal binding enzymatic domains in essential bacterial drug targets [19, 20].…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and microbiological evaluation of ampicillin–tetramic acid hybrid antibiotics

et al. 2016

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Exploiting iron-uptake pathways by conjugating β-lactam antibiotics with iron-chelators such as catechol and hydroxamic acid is a proven strategy to overcome permeability-related resistance in Gram-negative bacteria. Since naturally occurring iron chelating tetramic acids have not been previously examined for this purpose, an exploratory series of novel ampicillin-tetramic acid hybrids that structurally resemble ureidopenicillins was designed and synthesized. The new analogs were evaluated for the ability to chelate iron and their MIC activities determined against a representative panel of clinically significant bacterial pathogens. The tetramic acid β-lactam hybrids demonstrated a high affinity to iron in the order of 10−30 M3. The hybrids were less active against Gram-positive bacteria. However, against Gram-negative bacteria, their activity was species dependent with several hybrids displaying improved activity over ampicillin against wild-type Pseudomonas aeruginosa. The anti-Gram-negative activities of the hybrids improved in the presence of clavulanic acid revealing that the tetramic acid moiety did not provide added protection against β-lactamases. Additionally, the hybrids were found to be efflux pump substrates as their activities markedly improved against pump-inactivated strains. Unlike the catechol and hydroxamic acid siderophore β-lactam conjugates, the activities of the hybrids did not improve under iron-deficient conditions. These results suggest that the tetramic acid hybrids gain permeability via different membrane receptors, or they are out competed by native bacterial siderophores with stronger affinities for iron. This study provides a foundation for the further exploitation of the tetramic acid moiety to achieve novel β-lactam anti-Gram-negative agents, providing that efflux and β-lactamase mediated resistance is addressed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and microbiological evaluation of ampicillin–tetramic acid hybrid antibiotics

et al. 2016

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“…It belongs to the tetramic acid (TMA) compound class that includes diverse natural products such as reutericyclin active against Gram-positive pathogens including staphylococci, clostridia and streptococci 13–15 . The cellular targets of the antibacterial TMAs range from cell wall biosynthesis, DNA topoisomerase and RNA polymerase to membrane potential 15 . 5HE-C10-TMA in common with reutericyclin dissipates the cytoplasmic membrane potential and pH gradient, and is an iron(III) chelator 12 .…”

Section: Introductionmentioning

confidence: 99%

5-Hydroxyethyl-3-tetradecanoyltetramic acid represents a novel treatment for intravascular catheter infections due toStaphylococcus aureus

Zapotoczna¹,

Murray²,

Hogan³

et al. 2016

J. Antimicrob. Chemother.

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Objectives: Biofilm infections of intravascular catheters caused by Staphylococcus aureus may be treated with catheter lock solutions (CLSs). Here we investigated the antibacterial activity, cytotoxicity and CLS potential of 5-hydroxyethyl-3-tetradecanoyltetramic acid (5HE-C14-TMA) compared with the related compounds 3-tetradecanoyltetronic (C14-TOA) and 3-tetradecanoylthiotetronic (C14-TTA), which are variants of quorum sensing signalling molecules produced by Pseudomonas aeruginosa. Methods: Antibacterial activity and mechanism of action of 5HE-C14-TMA, C14-TOA and C14-TTA were determined via MIC, bacterial killing, membrane potential and permeability assays. Susceptibility of S. aureus biofilms formed in the presence of plasma in vitro was investigated, MTT cytotoxicity testing was undertaken and cytokine release in human blood upon exposure to 5HE-C14-TMA and/or S. aureus biofilms was quantified. The effectiveness of 5HE-C14-TMA as CLS therapy in vivo was assessed using a rat intravascular catheter biofilm infection model. Results: MICs of 5HE-C14-TMA, C14-TOA and C14-TTA ranged from 2 to 4 mg/L. 5HE-C14-TMA and C14-TTA were bactericidal; all three compounds perturbed the staphylococcal membrane by increasing membrane permeability, depolarized the transmembrane potential and caused ATP leakage. Cytotoxicity and haemolytic activity were compound and target cell type-dependent. 5HE-C14-TMA reduced S. aureus biofilm viability in a dose-dependent manner in vitro and in vivo and did not trigger release of cytokines in human blood, but inhibited the high levels of IL-8 and TNF-α induced by S. aureus biofilms. Conclusions: 5HE-C14-TMA, C14-TOA and C14-TTA are membrane-active agents. 5HE-C14-TMA was the most potent, eradicating S. aureus biofilms at 512–1024 mg/L both in vitro and in vivo as a CLS.

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“…Initially, given the highly lipophilic nature of the parent compounds and their structural similarities with antibiotics such as the reutericyclins, we sought to explore the effect of these compounds on membrane integrity. [28] We subjected the compounds to a red blood cell hemolysis assay (defibrinated sheep blood), [29] revealing less than 1% hemolysis at 40 μM for both natural product 1 and compound 29 . Furthermore, a BacLight ™ assay was utilized with S. aureus ATCC 29213 to evaluate the membrane permeabilization.…”

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confidence: 99%

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

et al. 2018

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Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

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Chemical Modulation of the Biological Activity of Reutericyclin: a Membrane-Active Antibiotic from Lactobacillusreuteri

Cited by 30 publications

References 32 publications

Design, synthesis and microbiological evaluation of ampicillin–tetramic acid hybrid antibiotics

Design, synthesis and microbiological evaluation of ampicillin–tetramic acid hybrid antibiotics

5-Hydroxyethyl-3-tetradecanoyltetramic acid represents a novel treatment for intravascular catheter infections due toStaphylococcus aureus

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

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