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Mechanism of polymyxin B resistance in Proteus mirabilis
Abstract:
The lipids from three types of organisms-a Proteus mirabilis wild type highly resistant to polymyxin B, a polymyxin B-sensitive mutant derived from the wild type, and the wild type grown in the presence of sulfadiazine resulting in phenotypic conversion to polymyxin B sensitivity-were examined to determine the nature of polymyxin B resistance. The phospholipid compositions were nearly identical; each organism contained similar small amounts of N-methyl phosphatidylethanolamine in addition to comparable quantities of phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. the fatty acid compositions were similar in the exponential phase of growth; in the stationary phase, sulfadiazine markedly inhibited the synthesis of cyclopropane fatty acids. Liposomes prepared from the dried lipids of the three types of organisms were extensively and similarly disrupted by the polymyxin. These findings suggest that polymyxin B resistance in P. mirabilis is determined by the cell envelope which prevents access of the antibiotic to the susceptible lipid target sites.
Insights
Polymyxin B resistance in Proteus mirabilis is not due to lipid changes but rather the cell envelope preventing antibiotic access. This finding impacts understanding bacterial antibiotic resistance mechanisms.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Polymyxin B is a critical antibiotic for treating infections caused by Gram-negative bacteria.
- Understanding the mechanisms of antibiotic resistance is crucial for developing effective treatments.
- Proteus mirabilis exhibits varying susceptibility to Polymyxin B.
Purpose of the Study:
- To investigate the lipid composition and cell envelope characteristics contributing to Polymyxin B resistance in Proteus mirabilis.
- To determine if alterations in phospholipid or fatty acid profiles confer resistance.
- To elucidate the role of the cell envelope in mediating Polymyxin B resistance.
Main Methods:
- Comparative analysis of lipid profiles (phospholipids and fatty acids) from wild-type resistant, sensitive mutant, and phenotypically converted Proteus mirabilis strains.
- Liposome disruption assays using Polymyxin B to assess lipid susceptibility.
- Growth phase analysis (exponential vs. stationary) to observe fatty acid synthesis variations.
Main Results:
- Phospholipid compositions were nearly identical across all tested strains.
- Fatty acid compositions were similar in the exponential phase, but sulfadiazine inhibited cyclopropane fatty acid synthesis in the stationary phase.
- Liposomes from all strains were similarly disrupted by Polymyxin B, indicating lipid targets are accessible in vitro.
Conclusions:
- Polymyxin B resistance in Proteus mirabilis is primarily mediated by the cell envelope.
- The cell envelope acts as a barrier, preventing Polymyxin B from reaching its susceptible lipid targets within the membrane.
- Lipid composition alone does not determine Polymyxin B resistance in this organism.