title: The protein synthesis inhibitors mycalamides A and E have limited susceptibility toward the drug efflux network.
abstract: The mycalamides belong to a family of protein synthesis inhibitors noted for antifungal, antitumour, antiviral, immunosuppressive, and nematocidal activities. Here we report a systematic analysis of the role of drug efflux pumps in mycalamide resistance and the first isolation of mycalamide E. In human cell lines, neither P-glycoprotein overexpression nor the use of efflux pump inhibitors significantly modulated mycalamide A toxicity in the systems tested. In Saccharomyces cerevisiae, it appears that mycalamide A is subject to efflux by the principle mediator of xenobiotic efflux, Pdr5p along with the major facilitator superfamily pump Tpo1p. Mycalamide E showed a similar efflux profile. These results suggest that future drugs based on the mycalamides are likely to be valuable in situations where efflux pump-based resistance leads to failure of other chemotherapeutic approaches, although efflux may be a mediator of resistance in antifungal applications.
authors.affiliation: Centre for Biodiscovery, Victoria University of Wellington, Wellington 6035, New Zealand.
authors.forename: Veronica
authors.initials: V
authors.lastname: Venturi
authors.forename: Carolina
authors.initials: C
authors.lastname: Davies
authors.forename: A Jonathan
authors.initials: AJ
authors.lastname: Singh
authors.forename: James H
authors.initials: JH
authors.lastname: Matthews
authors.forename: David S
authors.initials: DS
authors.lastname: Bellows
authors.forename: Peter T
authors.initials: PT
authors.lastname: Northcote
authors.forename: Robert A
authors.initials: RA
authors.lastname: Keyzers
authors.forename: Paul H
authors.initials: PH
authors.lastname: Teesdale-Spittle
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017353:Gene Deletion; D006801:Humans; D008387:Marine Toxins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011161:Porifera / Q000737:chemistry; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011714:Pyrans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D008387:Marine Toxins; D011500:Protein Synthesis Inhibitors; D011714:Pyrans; C573442:mycalamide E; C059646:mycalamide A