Academic Journal
Different Pathways Mediate Amphotericin-Lactoferrin Drug Synergy in Cryptococcus and Saccharomyces
| العنوان: | Different Pathways Mediate Amphotericin-Lactoferrin Drug Synergy in Cryptococcus and Saccharomyces |
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| المؤلفون: | Lai, YW, Pang, CNI, Campbell, LT, Chen, SCA, Wilkins, MR, Carter, DA |
| المصدر: | urn:ISSN:1664-302X ; Frontiers in Microbiology, 10, 2195 |
| بيانات النشر: | Frontiers |
| سنة النشر: | 2019 |
| المجموعة: | UNSW Sydney (The University of New South Wales): UNSWorks |
| مصطلحات موضوعية: | 3107 Microbiology, 3101 Biochemistry and Cell Biology, 31 Biological Sciences, Infectious Diseases, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Infection, Cryptococcus neoformans, RNA-Seq, Saccharomyces, amphotericin B, cellular stress response, drug synergy, lactoferrin, anzsrc-for: 3107 Microbiology, anzsrc-for: 3101 Biochemistry and Cell Biology, anzsrc-for: 31 Biological Sciences, anzsrc-for: 0502 Environmental Science and Management, anzsrc-for: 0503 Soil Sciences, anzsrc-for: 0605 Microbiology, anzsrc-for: 3207 Medical microbiology |
| الوصف: | Fungal infections are an increasing cause of morbidity and mortality. Current antifungal drugs are limited in spectrum, few new drugs are in development, and resistance is an increasing issue. Drug synergy can enhance available drugs and extend their lifetime, however, few synergistic combinations are in clinical use and mechanistic data on how combinations work is lacking. The multifunctional glycoprotein lactoferrin (LF) acts synergistically with amphotericin B (AMB) in a range of fungal species. Whole LF binds and sequesters iron, and LF can also be digested enzymatically to produce cationic peptides with distinct antimicrobial functions. To understand how LF synergizes AMB, we previously undertook a transcriptomic analysis in Saccharomyces and found a paradoxical down-regulation of iron and stress response, suggesting stress pathway interference was dysregulating an appropriate response, resulting in cell death. To extend this to a fungal pathogen, we here perform the same analysis in Cryptococcus neoformans. While both fungi responded to AMB in a similar way, the addition of LF produced remarkably contrasting results, with the Cryptococcus transcriptome enriched for processes relating to cellular stress, up-regulation of endoplasmic-reticulum-associated protein degradation (ERAD), stress granule disassembly and protein folding, endoplasmic reticulum-Golgi-vacuole trafficking and autophagy, suggesting an overall disruption of protein and lipid biosynthesis. These studies demonstrate that the mechanism of LF-mediated synergy is species-specific, possibly due to differences in the way LF peptides are generated, bind to and enter cells and act on intracellular targets, illustrating how very different cellular processes can underlie what appears to be a similar phenotypic response. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | http://purl.org/au-research/grants/nhmrc/APP1021267; http://hdl.handle.net/1959.4/unsworks_61703; https://doi.org/10.3389/fmicb.2019.02195 |
| DOI: | 10.3389/fmicb.2019.02195 |
| الاتاحة: | http://hdl.handle.net/1959.4/unsworks_61703 https://doi.org/10.3389/fmicb.2019.02195 |
| Rights: | open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.6D32BAE6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3389/fmicb.2019.02195 |
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