Polymyxins: Mode of Action

Li, Zhifeng; Velkov, Tony

doi:10.1007/978-3-030-16373-0_4

Cited by 38 publications

(32 citation statements)

References 99 publications

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“…S1A). Polymyxins bind the lipid A moiety of LPS, displacing divalent cations, disrupting the integrity of LPS-crosslinks, and resulting in an increase in membrane permeability (Newton 1953; Dixon and Chopra 1986; Trimble et al 2016; Li and Velkov 2019). We posited that if the transposon disrupts a gene required for the maintenance of cell envelope integrity, the resulting mutant will become more susceptible to polymyxin B, and the gene would be identified through our TIS screen as these mutants will be outcompeted during growth; identifiable as a depletion in transposon-insertions.…”

Section: Resultsmentioning

confidence: 99%

YhcB coordinates peptidoglycan and LPS biogenesis with phospholipid synthesis duringEscherichia colicell growth

Goodall

Isom

Rooke

et al. 2021

Preprint

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The cell envelope is essential for viability in all kingdoms of life. It retains enzymes and substrates within a confined space while providing a protective barrier to the external environment. Destabilising the envelope of bacterial pathogens is a common strategy employed by antimicrobial treatment. However, even in one of the most well studied organisms, Escherichia coli, there remain gaps in our understanding of how the synthesis of the successive layers of the cell envelope are coordinated during growth and cell division. Here, we used a whole genome phenotypic screen to identify mutants with a defective cell envelope. We report that loss of yhcB, a conserved gene of unknown function, results in loss of envelope stability, increased cell permeability and dysregulated control of cell size. Using whole genome transposon mutagenesis strategies we report the complete genetic interaction network of yhcB, revealing all genes with a synthetic negative and a synthetic positive relationship. These genes include those previously reported to have a role in cell envelope biogenesis. Surprisingly, we identified genes previously annotated as essential that became non-essential in a ΔyhcB background. Subsequent analyses suggest that YhcB sits at the junction of several envelope biosynthetic pathways coordinating the spatiotemporal growth of the cell, highlighting YhcB as an as yet unexplored antimicrobial target.

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Section: Resultsmentioning

confidence: 99%

YhcB coordinates peptidoglycan and LPS biogenesis with phospholipid synthesis duringEscherichia colicell growth

Goodall

Isom

Rooke

et al. 2021

Preprint

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“…Thus, to either modify these drugs or develop completely novel antibiotics, it is timely to establish a molecular-level understanding of each stage of the process via which they bring about bacterial cell death. To date, mechanistic studies of PMB1 have focused almost entirely on the two membranes of Gram-negative bacteria (Trimble et al, 2016;Li and Velkov, 2019). From a simulation perspective, the slowly diffusing nature of the lipopolysaccharide (LPS) molecules in the outer leaflet of the OM renders it difficult to achieve the timescales required to observe penetration into, let alone crossing of, the OM at atomistic or even coarse-grained resolution (Berglund et al, 2015;Jefferies et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The hitchhiker's guide to the periplasm: Unexpected molecular interactions of polymyxin B1 in E. coli

Pedebos

Smith²,

Boags³

et al. 2021

Structure

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“…Further studies are in progress to assess SB, SS and AS as adjuvants to polybasic/cationic antimicrobial peptides and antibiotics that have a self-promoted uptake mechanism, such as colistin. 54,55…”

Section: Discussionmentioning

confidence: 99%

Aspirin, sodium benzoate and sodium salicylate reverse resistance to colistin in Enterobacteriaceae andPseudomonas aeruginosa

Malla

Mireles

Ramírez

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background MDR bacterial infections are currently a serious problem for clinicians worldwide. Klebsiella pneumoniae and Enterobacter spp., among Enterobacteriaceae, and Pseudomonas aeruginosa, are part of the group of ESCAPE pathogens or bacteria that ‘escape’ from common antibacterial treatments. The lack of effectiveness of the first common line of antibiotics has led to the search for new therapies based on older antibiotics, such as colistin. Objectives We searched for new enhancers of the action of colistin against MDR Gram-negative bacteria that can be easily applicable to clinical treatments. Methods Colistin MICs were determined alone and with the protonophores CCCP, sodium benzoate, sodium salicylate and aspirin using the broth microdilution method and FIC indexes were calculated to assess synergy between colistin and each chemical. Time–kill assays of colistin with and without protonophores were performed to determine the bactericidal action of combinations of colistin with protonophores. Likewise, the effect of sucrose, l-arginine and l-glutamic acid on the MICs of colistin alone and combined with each protonophore was assessed. Results It was found that sodium benzoate, sodium salicylate and aspirin, at concentrations allowed for human and animal use, partially or totally reversed resistance to colistin in P. aeruginosa and highly resistant enterobacterial strains. The mechanism of action could be related to their negative charge at a physiological pH along with their lipid-soluble character. Conclusions Sodium benzoate, sodium salicylate and aspirin are good enhancers to use in antibiotic therapies that include colistin.

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Polymyxins: Mode of Action

Cited by 38 publications

References 99 publications

YhcB coordinates peptidoglycan and LPS biogenesis with phospholipid synthesis duringEscherichia colicell growth

YhcB coordinates peptidoglycan and LPS biogenesis with phospholipid synthesis duringEscherichia colicell growth

The hitchhiker's guide to the periplasm: Unexpected molecular interactions of polymyxin B1 in E. coli

Aspirin, sodium benzoate and sodium salicylate reverse resistance to colistin in Enterobacteriaceae andPseudomonas aeruginosa

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