title: Synergy of the antibiotic colistin with echinocandin antifungals in Candida species.
abstract: OBJECTIVE
  Candida albicans is the most prevalent fungal pathogen of humans, causing a wide range of infections from harmless superficial to severe systemic infections. Improvement of the antifungal arsenal is needed since existing antifungals can be associated with limited efficacy, toxicity and antifungal resistance. Here we aimed to identify compounds that act synergistically with echinocandin antifungals and that could contribute to a faster reduction of the fungal burden.
  
  
  METHODS
  A total of 38 758 compounds were tested for their ability to act synergistically with aminocandin, a β-1,3-glucan synthase inhibitor of the echinocandin family of antifungals. The synergy between echinocandins and an identified hit was studied with chemogenomic screens and testing of individual Saccharomyces cerevisiae and C. albicans mutant strains.
  
  
  RESULTS
  We found that colistin, an antibiotic that targets membranes in Gram-negative bacteria, is synergistic with drugs of the echinocandin family against all Candida species tested. The combination of colistin and aminocandin led to faster and increased permeabilization of C. albicans cells than either colistin or aminocandin alone. Echinocandin susceptibility was a prerequisite to be able to observe the synergy. A large-scale screen for genes involved in natural resistance of yeast cells to low doses of the drugs, alone or in combination, identified efficient sphingolipid and chitin biosynthesis as necessary to protect S. cerevisiae and C. albicans cells against the antifungal combination.
  
  
  CONCLUSIONS
  These results suggest that echinocandin-mediated weakening of the cell wall facilitates colistin targeting of fungal membranes, which in turn reinforces the antifungal activity of echinocandins.
authors: Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, F-75015 Paris, France.
authors: Ute
authors: U
authors: Zeidler
authors: Marie-Elisabeth
authors: ME
authors: Bougnoux
authors: Alexandru
authors: A
authors: Lupan
authors: Olivier
authors: O
authors: Helynck
authors: Antonia
authors: A
authors: Doyen
authors: Zacarias
authors: Z
authors: Garcia
authors: Natacha
authors: N
authors: Sertour
authors: Cécile
authors: C
authors: Clavaud
authors: Hélène
authors: H
authors: Munier-Lehmann
authors: Cosmin
authors: C
authors: Saveanu
authors: Christophe
authors: C
authors: d'Enfert
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002175:Candida / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002473:Cell Wall / Q000187:drug effects; D002686:Chitin / Q000096:biosynthesis; D003091:Colistin / Q000494:pharmacology* / Q000627:therapeutic use; D004396:Coloring Agents; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology* / Q000627:therapeutic use; D015723:Gene Library; D056084:Genetic Fitness; D005838:Genotype; D007201:Indicator Dilution Techniques; D055666:Lipopeptides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D011419:Propidium; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D013107:Sphingolipids / Q000096:biosynthesis
chemical_list: D000935:Antifungal Agents; D004396:Coloring Agents; D054714:Echinocandins; D055666:Lipopeptides; D013107:Sphingolipids; C476911:aminocandin; D002686:Chitin; D011419:Propidium; D003091:Colistin
keywords: Candida albicans; caspofungin; combination therapy; polymyxin; sphingolipids