Biology subjects

Fridman, M.

Publications and source records attributed to Fridman, M..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial cardiolipin sequestration of caspofungin underlies Cryptococcus neoformans inherent resistance and may contribute to cardiotoxicity

Cryptococcus exhibits inherent resistance to the echinocandin, caspofungin, which inhibits the synthesis of (1,3)-{beta}-D-glucan, a key component of the polysaccharide cell wall. The essential FKS1 gene encodes the catalytic subunit of (1,3)-{beta}-D-glucan synthase and caspofungin effectively inhibits its activity in vitro, yet the drug remains ineffective against Cryptococcus, suggesting mechanisms beyond target insensitivity. The underlying mechanisms of caspofungin resistance remain unknown, although altered regulation of cell-wall remodeling genes, plasma membrane modifications, drug efflux pathways, and melanin biosynthesis have been suggested. Using boron dipyrromethene (BD-) and fluorescein (F-) labelled caspofungin, we demonstrate that caspofungin enters the cryptococcal cell and primarily accumulates in the mitochondrial inner membrane rather than the plasma membrane. We further establish that this mitochondrial accumulation is driven by a specific interaction between caspofungin and cardiolipin, a phospholipid found in mitochondrial membranes. We demonstrate that this unforeseen localization indicates that mitochondrial sequestration diminishes the effective drug concentrations at the intended target. Notably, the interaction between caspofungin and cardiolipin also takes place in human cells, establishing a mechanistic connection to caspofungin-related cardiotoxicity. Our findings reveal a previously unrecognized mechanism of echinocandin resistance in Cryptococcus and emphasize cardiolipin as an important factor in caspofungin effectiveness.

microbiology↗

bioRxiv2021

Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin

Aspergillus fumigatus is the main causative agent of invasive pulmonary aspergillosis (IPA), a severe disease that affects immunosuppressed patients worldwide. The fungistatic drug caspofungin is the second line therapy against IPA but has increasingly been used against clinical strains that are resistant to azoles, the first line antifungal therapy. In high concentrations, caspofungin induces a tolerance phenotype with partial reestablishment of fungal growth called caspofungin paradoxical effect (CPE), resulting from a change in the composition of the cell wall. An increasing number of studies has shown that different isolates of A. fumigatus exhibit phenotypic heterogeneity, including heterogeneity in their CPE response. To gain insights into the underlying molecular mechanisms of CPE response heterogeneity, we analyzed the transcriptomes of two A. fumigatus reference strains, Af293 and CEA17, exposed to low and high caspofungin concentrations. We found that there is a core transcriptional response that involves genes related to cell wall remodeling processes, mitochondrial function, transmembrane transport, and amino acid and ergosterol metabolism, and a variable response related to secondary metabolite (SM) biosynthesis and iron homeostasis. Specifically, we show here that the overexpression of a SM pathway that works as an iron chelator extinguishes the CPE in both backgrounds, whereas iron depletion is detrimental for the CPE in Af293 but not in CEA17. We next investigated the function of the transcription factor CrzA, whose deletion was previously shown to result in heterogeneity in the CPE response of the Af293 and CEA17 strains. We found that CrzA constitutively binds to and modulates the expression of several genes related to processes involved in caspofungin tolerance, and that crzA deletion differentially impacts the SM production and growth of Af293 and CEA17. As opposed to the {Delta}crzACEA17 mutant, the {Delta}crzAAf293 mutant fails to activate cell wall remodeling genes upon caspofungin exposure, which most likely severely affects its macrostructure and extinguishes its CPE. This work describes how heterogeneity in the response to an antifungal agent between A. fumigatus strains stems from heterogeneity in the function of a transcription factor and its downstream target genes.

microbiology↗

bioRxiv2019

The Role of the Public Health Service Equalization Program in the Control of Hypertension in China: Results from a Cross-sectional Health Interview Survey

ObjectivesNon-communicable diseases (NCDs) have become the main cause of mortality in China. In 2009, the Chinese government introduced the Public Health Service Equalization (PHSE) program to restore the primary healthcare system in both essential medical care and public health service provision. This study evaluates the impact of management on hypertension control and evaluate how the program works.\n\nMethodsThe China National Health Development Research Centre (CNHDRC) undertook the Cross-sectional Health Service Interview Survey (CHSIS) of 62,097 people from primary healthcare reform pilot areas, across 17 provinces from eastern, central and western parts of China in 2014. This study is based on CHSIS survey responses from 9,607 participants, who had been diagnosed with hypertension. Regression analysis was used to estimate the impact of management provided under PHSE on hypertension control adjusting for the effects of other known determinants of hypertension control.\n\nFindingsUncontrolled hypertension was markedly lower among respondents, whose hypertension had been managed (22.4% in managed patients versus 31.1% in unmanaged patients, p<0.001). The interaction between PHSE management and the geographical region was highly significant in the model (p<0.001), suggesting that the PHSE program was not equally effective in all regions. Further analysis suggested that approximately 10% of regional variability was attributed to differences in administrative systems, as there was a significant association (P=0.014) between the presence of established regional Information Management Systems (IMS) and increased PHSE effectiveness. Insurance ({chi}2(5)=4.4, p=0.496) and Hukou ({chi}2(1)=2.4, p=0.121), which denote social security and urban rural differences, respectively, were not significant predictor of hypertension control.\n\nConclusionActive management of hypertension through the PHSE program was effective with 7.31 million more patients receiving hypertension control and equalization of service delivery was reflected to some extent. The link between established IMS and regional variability in the impact of PHSE highlights the importance of effective management of patient referrals and follow-up. Further investigation is needed to explore the factors that influence the effectiveness of PHSE.

scientific communication and education↗