“…This led us to speculate that metergoline conditionally targets the bacterial cytoplasmic membrane in outer membrane-disrupted cells, in line with previous observations of antibiotic-induced bacterial lysis attributed to imbalanced proton homeostasis across this membrane 41,42 . This hypothesis would be consistent with the crypic antifungal activity of metergoline that is related, in part, to depolarization of mitochondrial membrane potential 43 .Fig. 5Metergoline is bacteriolytic and perturbs the S .…”
Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.
“…This led us to speculate that metergoline conditionally targets the bacterial cytoplasmic membrane in outer membrane-disrupted cells, in line with previous observations of antibiotic-induced bacterial lysis attributed to imbalanced proton homeostasis across this membrane 41,42 . This hypothesis would be consistent with the crypic antifungal activity of metergoline that is related, in part, to depolarization of mitochondrial membrane potential 43 .Fig. 5Metergoline is bacteriolytic and perturbs the S .…”
Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.
“…The Ras-cAMP-PKA signaling pathway 315 and the bZip transcription factor Cap1 316 317 have also been implicated in distinct apoptotic scenarios. Finally, other closely related Candida species, e.g., Candida glabrata 318 , Candida krusei 319 , Candida dubliniensis 320 , Candida tropicalis 321 , or Candida parapsilosis 232 322 , have been reported to exhibit apoptotic markers upon lethal challenge.…”
Section: Rcd In Other Yeasts and Filamentous Fungimentioning
Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research.
“…that are reported to induce ROS are 7-chlorotetrazolo-[5,1-c]benzo[1,2,4]triazine [68][69][70], the serotoninereceptor antagonist metergoline [71], dihydrosphingosine (DHS; and its analogs) and phytosphingosine [72,73], piperazine-1-carboxyamidine derivatives [74] and hydroxypyridones [75]. Furthermore, metergoline, DHS and phytosphingosine induce apoptosis in Candida krusei [71] and Aspergillus nidulans, respectively [72]. For the DHS analogs and the piperazine-1-carboxyamidine derivatives, a direct correlation between antifungal activity and ROS accumulation was found using the antioxidant ascorbic acid [73,74].…”
Invasive fungal infections are associated with very high mortality rates ranging from 20-90% for opportunistic fungal pathogens such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Fungal resistance to antimycotic treatment can be genotypic (due to resistant strains) as well as phenotypic (due to more resistant fungal lifestyles, such as biofilms). With regard to the latter, biofilms are considered to be critical in the development of invasive fungal infections. However, there are only very few antimycotics, such as miconazole (azoles), echinocandins and liposomal formulations of amphotericin B (polyenes), which are also effective against fungal biofilms. Interestingly, these antimycotics all induce reactive oxygen species (ROS) in fungal (biofilm) cells. This review provides an overview of the different classes of antimycotics and novel antifungal compounds that induce ROS in fungal planktonic and biofilm cells. Moreover, different strategies to further enhance the antibiofilm activity of such ROS-inducing antimycotics will be discussed.
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