Potentiation of Antibiotics against Gram-Negative Bacteria by Polymyxin B Analogue SPR741 from Unique Perturbation of the Outer Membrane.
Shawn FrenchMaya FarhaMichael J EllisZaid SameerJean-Philippe CôtéNicole CotroneoTroy ListerAileen RubioEric D BrownPublished in: ACS infectious diseases (2019)
Therapeutics targeting Gram-negative bacteria have the challenge of overcoming a formidable outer membrane (OM) barrier. Here, we characterize the action of SPR741, a novel polymyxin B (PMB) analogue shown to potentiate several large-scaffold antibiotics in Gram-negative pathogens. Probing the surface topology of Escherichia coli using atomic force microscopy revealed substantial OM disorder at concentrations of SPR741 that lead to antibiotic potentiation. Conversely, very little cytoplasmic membrane depolarization was observed at these same concentrations, indicating that SPR741 acts predominately on the OM. Truncating the lipopolysaccharide (LPS) core with genetic perturbations uniquely sensitized E. coli to SPR741, suggesting that LPS core residues keep SPR741 at the OM, where it can potentiate a codrug, rather than permit its entry to the cytoplasmic membrane. Further, a promoter activity assay revealed that SPR741 challenge induced the expression of RcsAB, a stress sensor for OM perturbation. Together, these results indicate that SPR741 interacts predominately with the OM, in contrast to the dual action of PMB and colistin at both the outer and cytoplasmic membranes.
Keyphrases
- gram negative
- escherichia coli
- multidrug resistant
- atomic force microscopy
- inflammatory response
- pseudomonas aeruginosa
- drug resistant
- gene expression
- magnetic resonance
- magnetic resonance imaging
- single cell
- single molecule
- cancer therapy
- long non coding rna
- transcription factor
- lps induced
- toll like receptor
- staphylococcus aureus
- oxidative stress
- cystic fibrosis
- biofilm formation
- molecular dynamics simulations
- computed tomography
- drug induced
- copy number
- antimicrobial resistance