After a bacterial infection is established, a small percentage of the bacteria slow their metabolism in response to environmental stressors. This semi-dormant state affords increased tolerance to antibiotics, especially aminoglycosides, lending these bacteria the name persister cells. Over time, and often upon completion of a course of antibiotics, the persister cells reactivate, leading to recurrent, chronic, and increasingly aggressive infections. Persistence is one of many mechanisms contributing to increasing rates of antibiotic resistance in modern healthcare.

A recent publication by Wooseong Kim et al. describes the identification of two synthetic retinoids (vitamin A analogues) that kill both active and persister MRSA cells by disrupting the lipid bilayer of the cell membrane. The compounds showed potent in vitro bactericidal activity against MRSA strain MW2, 100% protection against MW2 infection-mediated death in C. elegans, and preclinical efficacy against a MW2 thigh infection in mice when administered via intraperitoneal injection.

The antimicrobial activity and cytoxicity of the retinoids are due to the polarity of the branch groups, which anchor the retinoids to the hydrophilic heads of the membrane bilayer. The retinoids can then penetrate the bilayer and wedge themselves between the lipid tails, inducing membrane perturbations and permeability. The authors hypothesize that this permeability explains the synergism observed between the compounds and gentamicin, as disruptions in the membrane allow for increased passive diffusion into the cell.

Modulation of the branch groups may further improve the bioactivity of the retinoids against MRSA and other Gram-positive infections. One potential obstacle to the development of synthetic retinoids as antibiotics is cytotoxicity. Although the compounds have demonstrated relative selectivity in studies so far, they may have the ability to disturb the membranes of healthy, human cells in addition to those of bacterial cells.

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