Promysalin is a salicylate-containing antimicrobial with a cell-membrane-disrupting mechanism of action on Gram-positive bacteria

Abstract

Promysalin was previously described as a narrow spectrum molecule with a unique species-specific activity against Pseudomonas aeruginosa. Here we demonstrate that promysalin is active against Gram-positive and Gram-negative bacteria using a microdilution assay. Promysalin acts on Gram-positive bacteria with a mechanism of action involving cell membrane damage with leakage of intracellular components. The evaluation of MICs and MBCs on 11 promysalin analogs, synthesized utilizing diverted total synthesis, allowed the identification of the structural moieties potentially involved in cell membrane interaction and damage. The mechanism of action of promysalin against Gram-negative bacteria is still not clarified, even if a synergistic effect with the bisguanidine chlorhexidine on cell membrane disruption has been observed.

Antimicrobial activity of resveratrol-derived monomers and dimers against foodborne pathogens

“…After incubation, the leakage of cFSE fluorescence outside the cells, as a result of membrane damage, was monitored by a fluorometer (Fig. 4) 32,33 . Pterostilbene 2 , its regioisomer 9 , and dimer 15 were able to determine a significant (P < 0.001) release of cFSE in all gram-positive strains tested, with 15 and chlorhexidine being the most active compounds.…”

“…Indeed, it is well documented that the accumulation of phenolic compounds in the lipid bilayer causes alterations in the membrane structure and could accelerate the extensive leakage of intracellular constituents, eventually leading to cell death 31 . Therefore, we assessed the damage to the gram-positive bacterial cell membrane after 30 min of exposure to the antimicrobials by measuring the efflux of the cFSE fluorescent molecule 33 . Among the tested compounds, dimer 15 was the most efficient at inducing cFSE leakage, whereas monomers 2 and 9 showed less significant cell membrane damage.…”

“…After 30 min of incubation, 1 mL of sample was used to measure cFSE fluorescence cell leakage. Briefly, the sample was centrifuged (13000 rpm, 2 min), and the cell-free supernatant was transferred to a 96-microtiter plate for the measurement of cFSE fluorescence in a Victor 3 fluorometer (PerkinElmer) 32,33 . The fluorescence data were calculated as the average of three independent assays and expressed as arbitrary units of fluorescence ± standard deviation.…”

Chemical and Biological Aspects of Nutritional Immunity—Perspectives for New Anti‐Infectives that Target Iron Uptake Systems

“…However, the mechanism was not elucidated in detail. The total synthesis of promysalin ( 88 ) and a series of analogues have recently been reported and their antimicrobial activities evaluated …”

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

“…Es wurde daher diskutiert, dass 88 Siderophortransportwege inhibiert und dadurch die Fähigkeit des Organismus,E isen zu erwerben, stark beeinträchtigt. [168][169][170][171] In Gram-positiven Bakterien, wie Staphylococcus aureus, hängen Tr ansportsysteme füre ssenzielle Metallionen typischerweise von Substratbindeproteinen (SBP) und einem ABC-Transporter ab (Abbildung 1). Die Totalsynthese von Promysalin (88) und einer Serie von Analoga und die Evaluierung ihrer antimikrobiellen Aktivitäten wurden kürzlich publiziert.…”