Review
Immunology
Herdson Renney de Sousa, Stefania de Frazao, Getulio Pereira de Oliveira Junior, Patricia Albuquerque, Andre Moraes Nicola
Summary: Cryptococcosis, caused by Cryptococcus spp, has a high mortality rate and lacks effective prevention and treatment methods. Understanding fungal virulence and host responses could lead to improved therapies. Studies using clinical isolates to correlate laboratory and patient data have provided valuable insights into the pathophysiology of cryptococcosis.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Microbiology
Hau Lam Choy, Elizabeth A. A. Gaylord, Tamara L. L. Doering
Summary: Cryptococcus neoformans is a pathogenic fungus that causes over 100,000 deaths worldwide each year. Only three drugs are available for treating cryptococcosis, but their usage is limited by factors such as toxicity, availability, cost, and resistance. Ergosterol, the most abundant sterol in fungi, plays a key role in modulating membrane behavior. We discovered a cryptococcal ergosterol transporter, Ysp2, and demonstrated its important roles in various aspects of cryptococcal biology and disease progression. These findings provide insights into the role of ergosterol homeostasis in the virulence of C. neoformans, expand our understanding of a pathway with therapeutic significance, and open up new research possibilities.
Review
Microbiology
Silvia Radosa, Falk Hillmann
Summary: Free living amoebae exhibit similarities with innate immune cells and may have served as a training ground for environmental pathogens. Virulence determinants of some fungal pathogens can resist both innate immune cells and environmental phagocytic predators.
CURRENT OPINION IN MICROBIOLOGY
(2021)
Article
Microbiology
Yina Wang, Maggie Wear, Gurkirat Kohli, Raghav Vij, Charles Giamberardino, Arpun Shah, Dena L. Toffaletti, Chen-Hsin A. Yu, John R. Perfect, Arturo Casadevall, Chaoyang Xue
Summary: The study reveals the importance of inositol catabolism in the virulence of Cryptococcus neoformans, with mutants lacking myo-inositol oxygenases showing altered capsule growth and polysaccharide structure. Utilization of inositol by the fungus may play a crucial role in its neurotropic pathogenicity.
Article
Biochemistry & Molecular Biology
Brian S. Mantilla, Karunakaran Kalesh, Nathaniel W. Brown, Dorothea Fiedler, Roberto Docampo
Summary: This study identified potential targets of 5-IP7 in Trypanosoma cruzi using pull-down experiments and mass spectrometry analysis, revealing new functional roles of 5-IP7 in this divergent eukaryote and providing potential new targets for chemotherapy.
MOLECULAR MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Desmarini Desmarini, Daniel Truong, Lorna Wilkinson-White, Chandrika Desphande, Mario Torrado, Joel P. Mackay, Jacqueline M. Matthews, Tania C. Sorrell, Sophie Lev, Philip E. Thompson, Julianne Teresa Djordjevic
Summary: New antifungals are urgently needed to treat invasive fungal infections. The fungal inositol polyphosphate kinase (IPK) pathway is a promising target. TNP and its analogues show inhibitory effects on IP3-4K from C. neoformans.
Article
Microbiology
Corinna Probst, Sarela Garcia-Santamarina, Jacob T. Brooks, Inge Van der Kloet, Oliver Baars, Martina Ralle, Dennis J. Thiele, J. Andrew Alspaugh
Summary: Copper homeostasis mechanisms are crucial for microbial adaptation during infection. In the opportunistic fungal pathogen Cryptococcus neoformans (Cn), the protein Cbi1/Bim1 is induced during copper limitation and plays a role in copper uptake. Our study suggests that Cbi1 is involved in regulating cell wall integrity and architecture, connecting copper homeostasis with adaptive changes within the fungal cell wall.
Article
Microbiology
Chen-Hsin Yu, Poppy Sephton-Clark, Jennifer L. Tenor, Dena L. Toffaletti, Charles Giamberardino, Miriam Haverkamp, Christina A. Cuomo, John R. Perfect
Summary: This study provides insights into the gene expression patterns of Cryptococcus neoformans in human cerebrospinal fluid, highlighting the importance of carbon metabolism, fatty acid synthesis, transport, cell wall structure, and stress-related gene functions during growth in this environment. Highly expressed yeast genes in human CSF include those associated with survival or virulence, as well as genes encoding hypothetical proteins. The findings contribute to understanding how the yeast responds to stress in the central nervous system, with potential implications for developing new therapeutics targeting these genes and pathways.
Review
Multidisciplinary Sciences
Davier Gutierrez-Gongora, Jennifer Geddes-McAlister
Summary: Cryptococcus neoformans is a globally important fungal pathogen that causes disease in immunocompromised individuals. Peptidases produced by this fungus play a crucial role in its virulence and can serve as potential targets for new therapeutic approaches.
Article
Multidisciplinary Sciences
Zhaobo Shi, Yong Sun, Hui Liu, Jun Zhang, Lili Ma
Summary: Cryptococcal meningoencephalitis (CM) is a highly fatal fungal infection that affects the central nervous system (CNS). It is mainly caused by Cryptococcus neoformans (C. neoformans) and can also occur in apparently immunocompetent patients. Complications such as cerebellar infarction and renal dysfunction may arise during the course of treatment, emphasizing the importance of close monitoring and timely intervention. In chronic hepatitis B virus (HBV) patients, CM may be a possible underlying pathogen, highlighting the need for awareness and appropriate management strategies.
Article
Medicine, Research & Experimental
Joseph Heitman
Summary: This Viewpoint is associated with the 25th anniversary of the American Society for Clinical Investigation's Stanley J. Korsmeyer Award, which recognizes scientific excellence, meritorious research, intellectual integrity, and mentoring of future researchers. The 2018 award honored Joseph Heitman for his contributions to understanding microbial pathogen evolution, disease causation, drug resistance, and discovery of immunosuppressive drug targets. Dr. Heitman has mentored numerous students, fellows, and researchers who have pursued successful careers in medicine and biomedical research.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Review
Biochemistry & Molecular Biology
Becky Tu-Sekine, Sangwon F. Kim
Summary: Cells rely on nutrients to provide energy and carbon building blocks, and interact with the inositol phosphate signaling network to meet cellular needs in response to energy storage.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Chemistry, Multidisciplinary
Israel Diniz-Lima, Leonardo Marques da Fonseca, Elias Barbosa da Silva-Junior, Joyce Cristina Guimaraes-de-Oliveira, Leonardo Freire-de-Lima, Danielle Oliveira Nascimento, Alexandre Morrot, Jose Osvaldo Previato, Lucia Mendonca-Previato, Debora Decote-Ricardo, Celio Geraldo Freire-de-Lima
Summary: Cryptococcosis is caused by pathogenic fungi, including Cryptococcus neoformans and Cryptococcus gattii. The latter causes severe undiscriminating infections in immunocompetent individuals and is becoming more prevalent due to climatic factors. The immunopathology of cryptococcosis caused by C. gattii is still poorly understood, but research has helped to uncover its different variants.
APPLIED SCIENCES-BASEL
(2022)
Article
Microbiology
Daniel Paiva Agustinho, Holly Leanne Brown, Guohua Chen, Elizabeth Anne Gaylord, Jennifer Geddes-McAlister, Michael Richard Brent, Tamara Lea Doering
Summary: This study used genetic methods to identify sequence variants that influence fungal virulence. The researchers found a region containing important variants and confirmed the significant impact of a specific variant on virulence.
CELL HOST & MICROBE
(2023)
Article
Microbiology
Iara Bastos de Andrade, Dario Correa-Junior, Vinicius Alves, Maria Helena Galdino Figueiredo-Carvalho, Marcos Vinicius Santos, Marcos Abreu Almeida, Alessandro Fernandes Valdez, Leonardo Nimrichter, Rodrigo Almeida-Paes, Susana Frases
Summary: This study investigated the effects of cyclosporine on Cryptococcus neoformans, finding that it altered the morphology, cell wall structure, and secretion characteristics of the fungus. Cyclosporine at half the minimum inhibitory concentration resulted in irregular shapes and elongated projections of yeast cells, increased chitin and lipid bodies in the fungal cell wall, and reduced cell body size, capsule diameter, and urease secretion. Additionally, cyclosporine affected the viscosity, electronegativity, and conductance of secreted polysaccharides. These findings highlight the significance of cyclosporine in shaping C. neoformans and its potential implications for antifungal drug development.
Article
Critical Care Medicine
Shizar Nahidi, Cristina Sotomayor-Castillo, Cecilia Li, Judy Currey, Rosalind Elliott, Ramon Z. Shaban
Summary: This study explored Australian critical care nurses' knowledge, preparedness, and experiences in managing patients with COVID-19. Most nurses reported good understanding of COVID-19 and had received specific training. Some nurses expressed concerns about SARS-CoV-2 infection and increased workload during the pandemic.
AUSTRALIAN CRITICAL CARE
(2022)
Article
Public, Environmental & Occupational Health
Cristina Sotomayor-Castillo, Cecilia Li, Keren Kaufman-Francis, Shizar Nahidi, Laurence J. Walsh, Sharon Ac Liberali, Eithne Irving, Alexander Cl Holden, Ramon Z. Shaban
Summary: This study examined the knowledge, preparedness, and experiences of dentists in Australia in managing COVID-19. Most dentists had a good level of knowledge about COVID-19 and sought up-to-date information from relevant websites. While the majority of dentists felt prepared to manage COVID-19 in the future, a significant number had not received training in the use of personal protective equipment. Some dentists reported feeling more stressed than usual and dealing with heavier workloads.
INFECTION DISEASE & HEALTH
(2022)
Article
Public, Environmental & Occupational Health
Katherine J. McKay, Cecilia Li, Cristina Sotomayor-Castillo, Patricia E. Ferguson, Mary Wyer, Ramon Z. Shaban
Summary: This study examined the acceptability of video monitoring for hand hygiene compliance among healthcare workers. The results showed that healthcare workers expressed concerns about punitive consequences, data security, and confidentiality. They also suggested that video systems may result in slower feedback but could also be used for feedback. Further exploration of the acceptability to patients is needed.
AMERICAN JOURNAL OF INFECTION CONTROL
(2023)
Article
Public, Environmental & Occupational Health
Katherine J. McKay, Cecilia Li, Ramon Z. Shaban
Summary: This study examined the utility of video-based monitoring systems for auditing hand hygiene compliance according to the WHO Five Moments. The findings suggest that auditing from recorded footage not only saves cost and time, but also reduces biases inherent in direct observation.
INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY
(2023)
Review
Microbiology
Justin Beardsley, Aiken Dao, Caitlin Keighley, Katherine Garnham, Catriona Halliday, Sharon C. -A. Chen, Tania C. Sorrell
Summary: Cryptococcus species are a significant cause of life-threatening infections, with Cryptococcus neoformans being the most common, and Cryptococcus gattii responsible for a significant number of cases worldwide. Despite optimal treatment, C. gattii infections have high early mortality rates. The lack of effective therapies and robust clinical and epidemiological data led to the classification of C. gattii as a medium-priority pathogen on the Fungal Priority Pathogen List released by the World Health Organization. This review summarizes the latest research on the taxonomy, epidemiology, pathogenesis, laboratory testing, and management of C. gattii infections.
Article
Chemistry, Medicinal
Nitin A. Patil, Wendong Ma, Xukai Jiang, Xiaoji He, Heidi H. Yu, Hasini Wickremasinghe, Jiping Wang, Philip E. Thompson, Tony Velkov, Kade D. Roberts, Jian Li
Summary: Polymyxins, including polymyxin B and colistin, are used as a last resort to treat life-threatening multidrug-resistant Gram-negative bacterial infections. However, their clinical use is limited by toxicity and increasing resistance. This study explores the role of the conserved position 10 threonine residue in polymyxin's structure and reveals the requirements for antibacterial activity. These findings provide vital information for developing safer and more effective next-generation polymyxin antibiotics.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Wenxiao K. Yue, Tianxia Zhang, Rekha Shandre Mugan, Nicholas Barlow, David K. Chalmers, Colin W. Pouton, Philip E. Thompson
Summary: Various strategies for peptide macrocyclization often require orthogonal protection or offer limited structural diversification. We have developed an efficient macrocyclization method using nucleophilic aromatic substitution to create thioether macrocycles. This versatile macrocyclization can be performed on unprotected peptidomimetics or resin-bound peptides, allowing for further modification and addition of functional groups. By applying this strategy, a library of potent melanocortin agonists with distinct subtype selectivity was successfully designed.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Medicine, General & Internal
Tania C. Sorrell, Martin Hensher, Lena A. Sanci
MEDICAL JOURNAL OF AUSTRALIA
(2023)
Article
Infectious Diseases
Mengyao Li, Mohammad A. K. Azad, Philip E. Thompson, Kade D. Roberts, Tony Velkov, Yan Zhu, Jian Li
Summary: Polymyxins are last-line antibiotics used to treat Gram-negative 'superbugs'. However, they can cause nephrotoxicity in up to 60% of patients. This study investigated the transcriptomic responses of human renal tubular cells to polymyxins and identified potential targets for designing safer new-generation polymyxins.
Article
Chemistry, Multidisciplinary
Liam Thomas Hales, Philip Evan Thompson
Summary: Developing straightforward yet flexible approaches to PROTAC synthesis can enhance the efficiency and quality of PROTAC development by incorporating structural elements of emerging designs. Solid-phase approaches may provide advantages over conventional synthesis methods if they can accommodate diverse chemistries and topographies.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Medicinal
Alicia Corlett, Jo-Anne Pinson, Marwa N. Rahimi, Jessica Van Zuylekom, Carleen Cullinane, Benjamin Blyth, Philip E. Thompson, Craig A. Hutton, Peter D. Roselt, Mohammad B. Haskali
Summary: This study synthesized and characterized a series of Lu-177-labeled peptides ([Lu-177]Lu-2b-4b) and compared them with the reference CCK(2)R-targeting peptide CP04 ([Lu-177]Lu-1b). [Lu-177]Lu-1b-4b showed high chemical purity, low Log D, strong binding affinity to CCK2R, and relatively high protein binding and internalization. Biodistribution studies showed that [Lu-177]Lu-2b-4b had higher uptake in tumors compared to CP04 at different time points. These findings suggest that [Lu-177]Lu-2b-4b could be a promising therapy for CCK2R-expressing tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Baolong Pan, Harshini Weerasinghe, Aysha Sezmis, Michael J. Mcdonald, Ana Traven, Philip Thompson, Claudia Simm
Summary: Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. This study identified a promising antifungal compound and its analogues, which showed improved efficacy against high-priority Candida species and inhibited fungal replication inside immune cells. The study also revealed the morphological and structural changes in resistant isolates, highlighting the importance of structure-activity relationship studies in expanding the repertoire of antifungal molecules with reduced cytotoxicity.
ACS INFECTIOUS DISEASES
(2023)
Article
Health Care Sciences & Services
J. M. Basseal, C. M. Bennett, P. Collignon, B. J. Currie, D. N. Durrheim, J. Leask, E. S. McBryde, P. McIntyre, F. M. Russell, D. W. Smith, T. C. Sorrell, B. J. Marais
Summary: Australia avoided the worst effects of COVID-19 pandemic, but still faced negative impacts. Lessons from Australia's public health response include the effectiveness of movement restrictions with careful consideration of adverse impacts, the value of disease modeling while acknowledging its limitations, the need for timely national data for reassessment of surveillance structures, the utility of advanced pathogen genomics and novel vaccine technology, the importance of evidence-informed and consultative decisionmaking, addressing major weaknesses in the aged-care sector, adequate infection prevention and control frameworks, prioritizing the interests of young people, recognizing epidemics as a standing threat, and fostering regional and global solidarity.
LANCET REGIONAL HEALTH-WESTERN PACIFIC
(2023)
Article
Chemistry, Medicinal
Wenxiao K. Yu, Tianxia Zhang, Rekha Shandre Mugan, Nicholas Barlow, David K. Chalmers, Colin W. Pouton, Philip E. Thompson
Summary: We have developed an efficient macrocyclization method utilizing nucleophilic aromatic substitution to create thioether macrocycles. This strategy is versatile and can be applied to unprotected peptidomimetics or resin-bound peptides. The resulting electron-withdrawing groups can be further used for orthogonal reactions, allowing for diversification and alteration of peptide properties. We applied this macrocyclization strategy to design melanocortin ligands, successfully generating a library of potent and selective agonists.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xukai Jiang, Nitin A. Patil, Yuwen Xu, Hasini Wickremasinghe, Qi Tony Zhou, Fanfan Zhou, Philip E. Thompson, Lushan Wang, Min Xiao, Kade D. Roberts, Tony Velkov, Jian Li
Summary: This study reveals that lung surfactant significantly reduces the antibacterial activity of polymyxins and uncovers the thermodynamics underlying this process. A new antibiotic, FADDI-235, is developed with potent activity against Gram-negative bacteria. These findings have important implications for treating bacterial pneumonia.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)