title: Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect.
abstract: OBJECTIVE
  The objective of this study was to identify existing clinical compounds that either possess a fungicidal activity alone or can act synergistically with fungistatic antifungals.
  
  
  METHODS
  We screened a clinical compound library for drugs that exhibited anti-Aspergillus activity. Among selected compounds, the cationic peptide antibiotic polymyxin B was chosen for further characterization because it can be used parenterally and topically. The fungicidal effect of polymyxin B and its synergistic interactions with azole antifungals were tested against a variety of fungal species. The toxicity of the drug combination of polymyxin B and fluconazole was compared with that of each drug alone in mammalian cell cultures.
  
  
  RESULTS
  We found that polymyxin B possesses a broad-spectrum antifungal activity at relatively high concentrations. However, because of its synergistic interactions with azole antifungals, polymyxin B at much lower concentrations exerts a potent fungicidal effect against Cryptococcus neoformans, Candida albicans and non-albicans Candida species and moulds when combined with azoles. The combination of polymyxin B and fluconazole at concentrations within susceptible breakpoints is particularly potent against C. neoformans isolates, including fluconazole-resistant strains. The drug combination displayed no additional toxicity compared with polymyxin B alone when tested in cell culture.
  
  
  CONCLUSIONS
  The combination of polymyxin B and fluconazole has the potential to be used in the clinic to treat systemic cryptococcosis. Our findings suggest that combining cationic peptide antibiotics with azole antifungals could provide a new direction for developing novel antifungal therapies.
authors.affiliation: Department of Biology, Texas A&M University, College Station, TX, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhai
authors.forename: Henry
authors.initials: H
authors.lastname: Zhou
authors.forename: Liangpeng
authors.initials: L
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Kathy
authors.initials: K
authors.lastname: Jung
authors.forename: Chou-Zen
authors.initials: CZ
authors.lastname: Giam
authors.forename: Xin
authors.initials: X
authors.lastname: Xiang
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Lin
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects*; D050296:Microbial Viability / Q000187:drug effects*; D011112:Polymyxin B / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole; D011112:Polymyxin B