Dimercaptosuccinic acid with membrane-targeting activity against Pseudomonas aeruginosa.

BACKGROUND

Multidrug resistant (MDR) gram-negative bacteria (GNB) are a serious health threat. GNB require divalent cations for the integrity of their outer membrane (OM), which can be inhibited by dimercaptosuccinic acid (DMSA), a sulfhydryl-containing metal chelator that has been used as an antidote to heavy metal toxicity. We aim to investigatethe effects and mechanisms of action of DMSA on Pseudomonas aeruginosa.

MAIN

METHODS

The inhibition of P. aeruginosa strains by DMSA was determined using growth kinetics analysis. Biofilm formation was evaluated using crystal violet staining after incubation for 24 h. We determined the bacterial OM permeability and cell membrane potential using propidium iodide (PI) and bis-(1,3-dibutylbarbituric acid) trimethineoxonol (DiBAC4(3)) staining, respectively, following DMSA exposure. The bioenergetics-related activity of DMSA-treated bacteria was assessed by determining intracellular ATP levels, bacterial motility and N-phenyl-naphtylamide (NPN) efflux assay.

RESULTS

DMSA inhibited the growth of bacteria in a concentration-dependent manner and repressed biofilm formation by P. aeruginosa. DMSA-treated bacteria exhibited increased PI uptake and enhanced DiBAC4(3) fluorescence intensity compared with untreated cells. Treatment of P. aeruginosa with DMSA reduced the intracellular ATP levels, bacterial motility, and efflux activity in the tested cells.

SIGNIFICANCE: The antibacterial mechanisms of DMSA may be related to alterations in OM permeability, membrane depolarization, and impaired bioenergetics-related activity, which are essential for bacterial viability and infection.