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Lipid X protects mice against fatal Escherichia coli infection
D T Golenbock1, J E Leggett, P Rasmussen
1Department of Medicine, University of Wisconsin-Madison.
Abstract:
Lipid X, the major monosaccharide precursor of lipid A, is nontoxic and has previously been shown to protect mice and sheep from the harmful effects of endotoxin. To test the hypothesis that lipid X could be therapeutic against infections with gram-negative organisms, neutropenic ICR mice were infected by intramuscular inoculation of Escherichia coli and subsequently treated with lipid X alone or in combination with the antibiotic ticarcillin. Lipid X slightly prolonged survival; treated mice had a significantly improved rate of survival 18 h after intramuscular inoculation as compared with controls (P less than 0.025). By 24 h, however, this difference disappeared. When lipid X was combined with ticarcillin, survival differences were both significant and prolonged. Treatment of mice with one to two doses of lipid X for a total dose of 1 mg intravenously and with 1,200 mg of ticarcillin per kg every 6 h improved survival over a 48-h treatment period from 5 to 23% (P less than 0.0025). Treatment with lipid X and ticarcillin over a broad range of antibiotic dosages in 362 mice demonstrated improved survival of two- to fourfold (P less than 0.0001 at 24 h after inoculation, P less than or equal to 0.0005 at 48 h, and P less than or equal to 0.0001 at 5 days). Lipid X enabled the dose of ticarcillin necessary to protect 50% of mice from death to be reduced by two- to fivefold. Pretreatment with lipid X was not necessary to improve survival: 16 of 17 (94%) infected and visibly ill animals that received lipid X and ticarcillin 6 h after thigh inoculation survived versus 30 of 44 (68%) control animals treated with ticarcillin alone (P less than 0.0001). Lipid X had no antimicrobial activity in vitro. Lipid X is a novel agent that enhances survival in an animal model of severe infection with gram-negative organisms.
Insights
Lipid X, a nontoxic endotoxin precursor, significantly enhanced survival in mice with gram-negative infections when combined with the antibiotic ticarcillin. This combination therapy proved effective even when administered after infection onset.
Area of Science:
- Microbiology
- Immunology
- Pharmacology
Background:
- Lipid X, a precursor to lipid A, is nontoxic and has demonstrated protective effects against endotoxin.
- Gram-negative bacterial infections pose significant health risks, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the therapeutic potential of Lipid X against Gram-negative bacterial infections.
- To determine if Lipid X enhances the efficacy of the antibiotic ticarcillin.
Main Methods:
- Neutropenic mice were infected with Escherichia coli and treated with Lipid X alone or with ticarcillin.
- Survival rates were assessed at various time points post-infection and treatment.
- Dose-response studies were conducted to evaluate the combined efficacy of Lipid X and ticarcillin.
Main Results:
- Lipid X alone showed a modest, short-term survival benefit.
- Combination therapy with Lipid X and ticarcillin significantly improved survival rates over extended periods (up to 5 days).
- Lipid X reduced the required dose of ticarcillin for effective treatment by two- to fivefold and improved survival even when treatment was initiated after visible illness.
Conclusions:
- Lipid X is a promising therapeutic agent that potentiates antibiotic efficacy against severe Gram-negative infections.
- The combination of Lipid X and ticarcillin offers a synergistic approach to managing these infections.
- Lipid X demonstrates therapeutic value independent of its in vitro antimicrobial activity.