title: New insights into the antibacterial mechanism of action of squalamine.
abstract: OBJECTIVE
  Antimicrobial resistance is an increasingly life-threatening problem that emphasizes the need to develop new antibacterial agents. The in vitro antibacterial activity of squalamine, a natural aminosterol, has been previously demonstrated against multidrug-resistant bacteria and moulds. Although the antibacterial activity of squalamine was found to correlate with that of other drugs, such as colistin, against Gram-negative bacteria, the former was active against Gram-positive bacteria, which are resistant to colistin. In this work, we provide new insights into squalamine's antibacterial mechanism of action compared with other known antibiotics.
  
  
  METHODS
  We evaluated squalamine's antibacterial mechanism of action using the broth microdilution method for MIC determination and time-kill assays, transmission electron microscopy for morphological change studies, bioluminescence for ATP release measurements and fluorescence methods for membrane depolarization assays.
  
  
  RESULTS
  Concerning Gram-negative bacteria, squalamine, similar to colistin, required interaction with the negatively charged phosphate groups in the bacterial outer membrane as the first step in a sequence of different events ultimately leading to the disruption of the membrane. Conversely, squalamine exhibited a depolarizing effect on Gram-positive bacteria, which resulted in rapid cell death.
  
  
  CONCLUSIONS
  The new insights into the mechanism of action of squalamine highlight the importance of aminosterols in the design of a new class of antibacterial compounds that could be used as disinfectants and detergents.
authors.affiliation: Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes URMITE UMR 6236 CNRS, Faculté de Pharmacie et de Médecine, Université de la Méditerranée, 27 boulevard Jean Moulin, 13385 Marseille 05, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Alhanout
authors.forename: Soazig
authors.initials: S
authors.lastname: Malesinki
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vidal
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Rolain
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002777:Cholestanols / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000166:cytology / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008853:Microscopy; D046529:Microscopy, Electron, Transmission; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D002777:Cholestanols; C079655:squalamine