Resistance of early stationary phase E. coli to membrane permeabilization by the antimicrobial peptide Cecropin A

Agrawal, Anurag; Rangarajan, N.; Weisshaar, James C.

doi:10.1016/j.bbamem.2019.05.012

Cited by 22 publications

(14 citation statements)

References 39 publications

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“…This suggests that the Salmonella outer membrane is remodeled during entry into stationary phase and becomes less reliant on cation-mediated cross-linking to maintain its permeability barrier to EtBr. Indeed, both Salmonella and E. coli become more resistant to CAMPs, whose mode of action relies upon interaction with negative charges on the LPS, in stationary phase ( 34 , 35 ).…”

Section: Resultsmentioning

confidence: 99%

Efflux Impacts Intracellular Accumulation Only in Actively Growing Bacterial Cells

Whittle

McNeil

Trampari

et al. 2021

mBio

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This study shows that efflux is important for maintaining low intracellular accumulation only in actively growing cells and that envelope permeability is the predominant factor in stationary-phase cells. This conclusion means that (i) antibiotics with intracellular targets may be less effective in complex infections with nongrowing or slow-growing bacteria, where intracellular accumulation may be low; (ii) efflux inhibitors may be successful in potentiating the activity of existing antibiotics, but potentially only for bacterial infections where cells are actively growing; and (iii) the remodeling of the cell envelope prior to stationary phase could provide novel drug targets.

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Section: Resultsmentioning

confidence: 99%

Efflux Impacts Intracellular Accumulation Only in Actively Growing Bacterial Cells

Whittle

McNeil

Trampari

et al. 2021

mBio

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“…As stationary phase bacterial cells are often resistant to several antibacterial agents 23 , we evaluated whether our α-MSH analogues retained their efficacy against E. coli cells at this particular phase in their growth. All the analogues at 10 µM concentrations were applied to the 10 5 CFU/mL stationary phase cells of E. coli , and the killing activity was observed.…”

Section: Resultsmentioning

confidence: 99%

Binding of cationic analogues of α-MSH to lipopolysaccharide and disruption of the cytoplasmic membranes caused bactericidal action against Escherichia coli

Tiwari

Singh

Kumar

et al. 2022

Sci Rep

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In earlier reports, we have shown the antimicrobial activity of a host neuropeptide, alpha-melanocyte stimulating hormone (α-MSH) and its cationic analogues against Staphylococcus aureus. These analogues of α-MSH showed enhanced staphylocidal activity without any significant mammalian cell toxicity. Therefore, here, we explored the antimicrobial activity of α-MSH and its cationic analogues against Escherichia coli. Though the presence of lipopolysaccharide (LPS) in Gram-negative bacteria enables them to resist most conventional antibiotics, encouragingly α-MSH and its four analogues showed killing of both logarithmic and stationary phase E. coli cells in a time, dose and cationicity-dependent manner. In fact, the most cationic analogue, KKK-MSH with a + 5 charge, demonstrated successful eradication of 105 CFU/mL of E. coli cells within 15 min at a concentration as low as 1 µM. BC displacement experiment revealed that cationicity of the peptides was directly related to the killing efficacy of these α-MSH analogues against E. coli cells via initial LPS-binding, leading to rapid disruption of the LPS-outer membrane complex followed by inner bacterial membrane damage and eventual cell death. Here, we propose α-MSH based cationic peptides as promising future agents with broad-spectrum antibacterial efficacy against both Gram-negative and Gram-positive pathogens.

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“…This suggests that the Salmonella outer membrane is remodelled during entry into stationary phase and becomes less reliant on cation-mediated crosslinking to maintain its permeability barrier to EtBr. Indeed, both Salmonella and E. coli become more resistant to CAMPs, whose mode of action relies upon interaction with negative charges on the LPS, in stationary phase 34,35…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that the Salmonella outer membrane is remodelled during entry into stationary phase and becomes less reliant on cationmediated crosslinking to maintain its permeability barrier to EtBr. Indeed, both Salmonella and E. coli become more resistant to CAMPs, whose mode of action relies upon interaction with negative charges on the LPS, in stationary phase 34,35 showed a delayed decrease in EtBr accumulation, although in stationary phase the two strains were similar. We conclude that in S. Typhimurium, although RpoS might play a role in envelope remodelling, it is not essential for generation of a lowpermeability envelope in stationary phase, so there are likely to be RpoS-dependent and -independent pathways to achieve this phenotype.…”

Section: Drug Accumulation In Stationary Phase Is Controlled By Reduced Membrane Permeabilitymentioning

confidence: 99%

Efflux only impacts drug accumulation in actively growing cells

Trampari

et al. 2021

Preprint

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For antibiotics with intracellular targets, effective treatment of bacterial infections requires the drug to accumulate to a high concentration inside cells. Bacteria produce a complex cell envelope and possess drug-export efflux pumps to limit drug accumulation inside cells. Decreasing cell envelope permeability and increasing efflux pump activity can reduce intracellular accumulation of antibiotics, and are commonly seen in antibiotic resistant strains. Here, we show that the balance between influx and efflux differs depending on bacterial growth phase in Gramnegative bacteria. Accumulation of the model fluorescent drug, ethidium bromide (EtBr) was measured in S. Typhimurium SL1344 (wild-type) and efflux deficient (ΔacrB) strains during growth. In SL1344, EtBr accumulation remained low, regardless of growth phase and did not correlate with acrAB transcription. EtBr accumulation in ΔacrB was high in exponential phase but dropped sharply later in growth, with no significant difference to SL1344 in stationary phase. Low EtBr accumulation in stationary phase was not due to the upregulation of other efflux pumps, but instead, due to decreased permeability of the envelope in stationary phase. RNAseq identified changes in expression of several pathways that remodel the envelope in stationary phase, leading to lower permeability. This study shows that efflux is only important for maintaining low drug accumulation in actively growing cells, and that envelope permeability is the predominant factor dictating the rate of drug entry in stationary phase cells. This conclusion means that (i) antibiotics with intracellular targets may be less effective in complex non-growing or slow-growing bacterial infections where intracellular accumulation may be low, (ii) efflux inhibitors may be successful in potentiating the activity of existing antibiotics, but potentially only for bacterial infections where cells are actively growing and (iii) the remodelling of the cell envelope prior to stationary phase could provide novel drug targets.

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Resistance of early stationary phase E. coli to membrane permeabilization by the antimicrobial peptide Cecropin A

Cited by 22 publications

References 39 publications

Efflux Impacts Intracellular Accumulation Only in Actively Growing Bacterial Cells

Efflux Impacts Intracellular Accumulation Only in Actively Growing Bacterial Cells

Binding of cationic analogues of α-MSH to lipopolysaccharide and disruption of the cytoplasmic membranes caused bactericidal action against Escherichia coli

Efflux only impacts drug accumulation in actively growing cells

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