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Inhibiting fatty acid synthesis overcomes colistin resistance
Lindsey A Carfrae1,2, Kenneth Rachwalski1,2, Shawn French1,2
1Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Abstract:
Treating multidrug-resistant infections has increasingly relied on last-resort antibiotics, including polymyxins, for example colistin. As polymyxins are given routinely, the prevalence of their resistance is on the rise and increases mortality rates of sepsis patients. The global dissemination of plasmid-borne colistin resistance, driven by the emergence of mcr-1, threatens to diminish the therapeutic utility of polymyxins from an already shrinking antibiotic arsenal. Restoring sensitivity to polymyxins using combination therapy with sensitizing drugs is a promising approach to reviving its clinical utility. Here we describe the ability of the biotin biosynthesis inhibitor, MAC13772, to synergize with colistin exclusively against colistin-resistant bacteria. MAC13772 indirectly disrupts fatty acid synthesis (FAS) and restores sensitivity to the last-resort antibiotic, colistin. Accordingly, we found that combinations of colistin and other FAS inhibitors, cerulenin, triclosan and Debio1452-NH3, had broad potential against both chromosomal and plasmid-mediated colistin resistance in chequerboard and lysis assays. Furthermore, combination therapy with colistin and the clinically relevant FabI inhibitor, Debio1452-NH3, showed efficacy against mcr-1 positive Klebsiella pneumoniae and colistin-resistant Escherichia coli systemic infections in mice. Using chemical genomics, lipidomics and transcriptomics, we explored the mechanism of the interaction. We propose that inhibiting FAS restores colistin sensitivity by depleting lipid synthesis, leading to changes in phospholipid composition. In all, this work reveals a surprising link between FAS and colistin resistance.
Insights
Fatty acid synthesis inhibitors, like MAC13772, can restore colistin sensitivity in resistant bacteria. Combining colistin with these inhibitors shows promise for treating multidrug-resistant infections.
Area of Science:
- Microbiology
- Molecular Biology
- Pharmacology
Background:
- Multidrug-resistant infections pose a significant threat, increasing mortality.
- Colistin resistance, particularly plasmid-borne mcr-1, is rising, limiting treatment options.
- Combination therapy is a promising strategy to restore antibiotic efficacy.
Purpose of the Study:
- To identify compounds that can resensitize colistin-resistant bacteria to colistin.
- To investigate the mechanism by which fatty acid synthesis inhibition restores colistin sensitivity.
- To evaluate the efficacy of combination therapy in preclinical models.
Main Methods:
- Screening of biotin biosynthesis inhibitors for synergy with colistin.
- Testing combinations of colistin with various fatty acid synthesis (FAS) inhibitors.
- In vivo efficacy studies in mouse models of infection.
- Chemical genomics, lipidomics, and transcriptomics for mechanistic insights.
Main Results:
- MAC13772 synergized with colistin against colistin-resistant bacteria by disrupting FAS.
- Combinations of colistin with other FAS inhibitors (cerulenin, triclosan, Debio1452-NH3) showed broad efficacy against chromosomal and plasmid-mediated resistance.
- Colistin and Debio1452-NH3 combination therapy was effective against mcr-1 positive Klebsiella pneumoniae and resistant Escherichia coli infections in mice.
- Inhibition of FAS was linked to altered phospholipid composition, restoring colistin sensitivity.
Conclusions:
- Fatty acid synthesis inhibition is a viable strategy to overcome colistin resistance.
- Combination therapy with colistin and FAS inhibitors offers a potential solution for multidrug-resistant infections.
- This study reveals a novel link between fatty acid synthesis and colistin resistance mechanisms.
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