Menu
×
John L. Dart Library
9 a.m. - 6 p.m.
Phone: (843) 722-7550
West Ashley Library
9 a.m. - 6 p.m.
Phone: (843) 766-6635
Folly Beach Library
9 a.m. - 1 p.m.
Phone: (843) 588-2001
Edgar Allan Poe/Sullivan's Island Library
Closed for renovations
Phone: (843) 883-3914
Wando Mount Pleasant Library
9 a.m. - 6 p.m.
Phone: (843) 805-6888
Village Library
9 a.m. - 6 p.m.
Phone: (843) 884-9741
St. Paul's/Hollywood Library
9 a.m. - 6 p.m.
Phone: (843) 889-3300
Otranto Road Library
9 a.m. - 6 p.m.
Phone: (843) 572-4094
Mt. Pleasant Library
9 a.m. – 6 p.m.
Phone: (843) 849-6161
McClellanville Library
9 a.m. - 1 p.m.
Phone: (843) 887-3699
Keith Summey North Charleston Library
9 a.m. – 6 p.m.
Phone: (843) 744-2489
John's Island Library
9 a.m. - 6 p.m.
Phone: (843) 559-1945
Hurd/St. Andrews Library
9 a.m. - 6 p.m.
Phone: (843) 766-2546
Miss Jane's Building (Edisto Library Temporary Location)
9 a.m. – 3 p.m.
Phone: (843) 869-2355
Dorchester Road Library
9 a.m. - 6 p.m.
Phone: (843) 552-6466
Baxter-Patrick James Island
9 a.m. - 6 p.m.
Phone: (843) 795-6679
Main Library
9 a.m. - 6 p.m.
Phone: (843) 805-6930
Bees Ferry West Ashley Library
9 a.m. - 6 p.m.
Phone: (843) 805-6892
Mobile Library
9 a.m. - 5 p.m.
Phone: (843) 805-6909
Today's Hours
John L. Dart Library
9 a.m. - 6 p.m.
Phone: (843) 722-7550
West Ashley Library
9 a.m. - 6 p.m.
Phone: (843) 766-6635
Folly Beach Library
9 a.m. - 1 p.m.
Phone: (843) 588-2001
Edgar Allan Poe/Sullivan's Island Library
Closed for renovations
Phone: (843) 883-3914
Wando Mount Pleasant Library
9 a.m. - 6 p.m.
Phone: (843) 805-6888
Village Library
9 a.m. - 6 p.m.
Phone: (843) 884-9741
St. Paul's/Hollywood Library
9 a.m. - 6 p.m.
Phone: (843) 889-3300
Otranto Road Library
9 a.m. - 6 p.m.
Phone: (843) 572-4094
Mt. Pleasant Library
9 a.m. – 6 p.m.
Phone: (843) 849-6161
McClellanville Library
9 a.m. - 1 p.m.
Phone: (843) 887-3699
Keith Summey North Charleston Library
9 a.m. – 6 p.m.
Phone: (843) 744-2489
John's Island Library
9 a.m. - 6 p.m.
Phone: (843) 559-1945
Hurd/St. Andrews Library
9 a.m. - 6 p.m.
Phone: (843) 766-2546
Miss Jane's Building (Edisto Library Temporary Location)
9 a.m. – 3 p.m.
Phone: (843) 869-2355
Dorchester Road Library
9 a.m. - 6 p.m.
Phone: (843) 552-6466
Baxter-Patrick James Island
9 a.m. - 6 p.m.
Phone: (843) 795-6679
Main Library
9 a.m. - 6 p.m.
Phone: (843) 805-6930
Bees Ferry West Ashley Library
9 a.m. - 6 p.m.
Phone: (843) 805-6892
Mobile Library
9 a.m. - 5 p.m.
Phone: (843) 805-6909
Patron Login
menu
Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.
Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
- Author(s): Tulloch, Lindsay B.; Tinti, Michele; Wall, Richard J.; Weidt, Stefan K.; Corpas- Lopez, Victoriano; Dey, Gourav; Smith, Terry K.; Fairlamb, Alan H.; Barrett, Michael P.; Wyllie, Susan
- Source:
PLoS Pathogens; 7/11/2024, Vol. 20 Issue 7, p1-23, 23p- Subject Terms:
- Source:
- Additional Information
- Abstract: Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of L. donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway. Author summary: The antifungal drug, amphotericin B, is also used in the treatment of visceral leishmaniasis, a potentially lethal parasitic disease infecting the specialised immune cells (macrophages) in the liver, spleen, and bone marrow. Treatment failures due to emerging drug resistance are a significant concern. Using a combination of genetic and biochemical approaches, we have confirmed the mechanisms by which these parasites become less sensitive to treatment with amphotericin B. In addition, we have identified a novel mechanism involving loss of a key enzyme (cytochrome P450 reductase 1) in the biosynthetic pathway to ergosterol, an important lipid component of the parasite's plasma membrane. These studies increase our fundamental understanding of this important metabolic pathway and provide information that may be exploited to develop novel therapeutic strategies to combat this killer disease. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Abstract:
Contact CCPL
Copyright 2022 Charleston County Public Library Powered By EBSCO Stacks 3.3.0 [350.3] | Staff Login
No Comments.