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FR-31564, a new phosphonic acid antibiotic: bacterial resistance and membrane permeability
Abstract:
Mutants which acquired resistance to FR-31564 were also resistant to fosfomycin and vice versa. Some exceptions to cross-resistance were found among clinical isolates of certain species. FR-31564 was found to be incorporated into bacterial cells more efficiently than fosfomycin although the extent of incorporation varied among species. In particular, the uptake rate of FR-31564 by a strain of Pseudomonas aeruginosa was ten times that of fosfomycin. The uptake rate of FR-31564 by both FR-31564- and fosfomycin-resistant mutants was less than one-tenth of that by the parent strain. FR-31564 was scarcely inactivated in the culture broths of FR-31564-resistant strains. All of the FR-31564-resistant mutants of P. aeruginosa came under the classification of strains lacking an L-alpha-glycerophosphate transport system.
Insights
New antibiotic FR-31564 shows cross-resistance with fosfomycin, indicating a shared bacterial resistance mechanism. FR-31564 uptake is more efficient but reduced in resistant mutants, linked to transport system deficiencies.
Area of Science:
- Microbiology
- Bacterial Physiology
- Antibiotic Resistance
Background:
- Fosfomycin is a broad-spectrum antibiotic with a unique mechanism of action.
- Understanding novel antibiotic resistance mechanisms is crucial for developing new treatments.
- FR-31564 is a novel compound with potential antibacterial activity.
Purpose of the Study:
- To investigate the resistance mechanisms of FR-31564.
- To determine the relationship between FR-31564 and fosfomycin resistance.
- To elucidate the role of bacterial uptake in FR-31564 efficacy.
Main Methods:
- Induction of resistance to FR-31564 and fosfomycin in bacterial strains.
- Cross-resistance studies between FR-31564 and fosfomycin.
- Measurement of antibiotic incorporation into bacterial cells.
- Analysis of L-alpha-glycerophosphate transport system in resistant mutants.
Main Results:
- Acquired resistance to FR-31564 conferred cross-resistance to fosfomycin, and vice versa, with some exceptions in clinical isolates.
- FR-31564 was incorporated into bacterial cells more efficiently than fosfomycin, with significant species-specific variations.
- Resistant mutants exhibited significantly reduced uptake rates for FR-31564.
- FR-31564-resistant Pseudomonas aeruginosa mutants lacked the L-alpha-glycerophosphate transport system.
Conclusions:
- FR-31564 and fosfomycin likely share a common transport system or mechanism of action, leading to cross-resistance.
- Bacterial resistance to FR-31564 can arise from decreased cellular uptake, potentially due to defects in the L-alpha-glycerophosphate transport system.
- Further research into the transport mechanisms of FR-31564 is warranted to understand its full therapeutic potential and resistance landscape.