tetramic-acid and reutericyclin

Reutericyclin is an inhibitory compound produced by sourdough isolates of Lactobacillus reuteri that is structurally but not functionally related to naturally occurring tetramic acids. It is bacteriostatic or bactericidal to gram-positive bacteria based on its activity as a proton-ionophore, and a broad range of food-related spoilage organisms and pathogens is inhibited by reutericyclin. Gram-negative bacteria are resistant to reutericyclin because of the barrier properties of their outer membrane, and resistance of beer-spoiling lactobacilli towards hop bitter acids provides cross-protection to reutericyclin. Remarkably, reutericyclin-producing strains were shown to persist for a period of 10 years in an industrial sourdough fermentation, and reutericyclin was shown to be produced in concentrations active against competitors during growth of L. reuteri in sourdough. Based on the known properties of reutericyclin and L. reuteri, reutericyclin-producing strains may have applications in the biopreservation of foods. Furthermore, these strains were shown to colonize reconstituted lactobacilli-free mice at high levels. Therefore, they could serve as a suitable model system to evaluate a possible impact of antimicrobial compounds on the intestinal microflora of humans and animals.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Food Microbiology; Food Preservation; Gram-Negative Bacteria; Gram-Positive Bacteria; Lactobacillus; Microbial Sensitivity Tests; Pyrrolidinones; Tenuazonic Acid

Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes.. A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action.. Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P < 0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole.. This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases.

Topics: Animals; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Colon; Disease Models, Animal; Male; Mesocricetus; Metronidazole; Pyrrolidinones; Tenuazonic Acid; Treatment Outcome

The potential for reutericyclin derivatives to be used as topical antibiotics to treat staphylococcal skin infections was investigated. All reutericyclins inhibited the growth of clinical isolates of drug-resistant Staphylococcus aureus. Unlike the standard topical agent mupirocin, most reutericyclin derivatives eradicated staphylococcal biofilms. Moreover, two compounds formulated in hydrophilic petrolatum (10%, wt/wt) were efficacious in treating S. aureus superficial skin infections in mice. These data exemplify the prospect of developing reutericyclins as new topical antibiotics.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Cell Line; Fibroblasts; Humans; Male; Mice; Pyrrolidinones; Staphylococcal Skin Infections; Tenuazonic Acid