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Molecular pathways affected by drugs that disrupt Na+ and lipid homeostasis in malaria parasites

Award Number: R01AI132508
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Molecular pathways affected by drugs that disrupt Na+ and lipid homeostasis in malaria parasites - Project Summary In recent years, several chemically diverse compounds have been identified that target PfATP4, a P-type ATPase involved in maintaining Na+ homeostasis in malaria parasites. Some of these compounds have advanced to clinical trials. Thus, PfATP4-active compounds are among the most attractive new antimalarials being developed to counter the continuing threat of drug resistance. Over the previous funding period, we have discovered some dramatic alterations in parasite physiology that accompany a short 2 h exposure to PfATP4 inhibitors. These include: i) Rapid alterations in lipid homeostasis within the parasites with reversible accumulation of cholesterol in the parasite plasma membrane (PPM); ii) Morphological changes resembling premature schizogony; and iii) Massive dephosphorylation of parasite proteins that may underlie the metabolic slowdown that follows PfATP4 inhibition. These observations reveal a collection of hitherto unknown interrelated molecular pathways, disruptions of which result in parasite demise. We found that PfATP4 inhibition appears to result in inhibition of PfNCR1, another druggable transporter, that is involved in maintaining lipid/cholesterol homeostasis within the PPM. Reduction of cholesterol content of the RBC plasma membrane results in dramatic expulsion of trophozoites from the host cell without the lysis of the RBC membrane. Remarkably, treatment with either PfATP4 or PfNCR1 inhibitors prevents this expulsion. These studies suggest an active transport of cholesterol between the RBC plasma membrane and the parasite. We found that trophozoite stage parasites exposed to PfATP4 inhibitors for just 2 h undergo massive morphological changes that resemble premature onset of schizogony events including the formation of inner membrane complexes, rhoptry-like structures and karyokinesis. In addition, trophozoites undergo massive reduction of a large number of metabolites suggestive of metabolic shutdown. We hypothesize that underlying all these events is a signaling cascade unleashed by the influx of Na+ into parasite cytoplasm following PfATP4 inhibition. In support of this proposition, we found dephosphorylation of a large number of proteins, prominent among which were molecules involved in DNA metabolism, chromosome segregation and cell cycle processes. The complexity of events triggered by PfATP4 inhibition requires a multidisciplinary approach. For this purpose, we have recruited outstanding co-investigators in consortium arrangements for the next funding period. Together, we propose to carry out the following specific aims: i) Investigate the relationship between cholesterol dynamics and its role in fatty acid and lipid transport in P. falciparum; ii) Explore the significance of dephosphorylation of proteins that follows PfATP4 inhibition; iii) Examine the causes of metabolic slowdown following PfATP4 inhibition; iv) Derive structural information for PfATP4 and PfNCR1 to understand molecular details about these validated antimalarial drug targets.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $665,638 )
2025	2025	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	8	12/12/2024	NON-COMPETING CONTINUATION	$665,638
														Subtotal = $665,638

Issue Date FY: 2024 ( Subtotal = $686,225 )
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	7	12/29/2023	NON-COMPETING CONTINUATION	$617,603
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	003	7	5/21/2024	NON-COMPETING CONTINUATION	$68,622
2024	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	6	2/22/2024	COMPETING CONTINUATION	$141,205
2024	2021	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	5	2/22/2024	NON-COMPETING CONTINUATION	-$141,205
														Subtotal = $686,225

Issue Date FY: 2023 ( Subtotal = $711,975 )
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	6	2/27/2023	COMPETING CONTINUATION	$0
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	6	1/13/2023	COMPETING CONTINUATION	$711,975
2023	2021	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	1/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $711,975

Issue Date FY: 2021 ( Subtotal = $588,304 )
2021	2021	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	3/31/2021	NON-COMPETING CONTINUATION	$588,304
														Subtotal = $588,304

Issue Date FY: 2020 ( Subtotal = $588,304 )
2020	2020	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	4/7/2020	NON-COMPETING CONTINUATION	$588,304
														Subtotal = $588,304

Issue Date FY: 2019 ( Subtotal = $588,304 )
2019	2019	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	4/11/2019	NON-COMPETING CONTINUATION	$588,304
														Subtotal = $588,304

Issue Date FY: 2018 ( Subtotal = $588,304 )
2018	2018	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	3/30/2018	NON-COMPETING CONTINUATION	$588,304
														Subtotal = $588,304

Issue Date FY: 2017 ( Subtotal = $588,304 )
2017	2017	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	5/4/2017	NEW	$588,304
														Subtotal = $588,304

Grand Total All Awards = $5,005,358

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Molecular pathways affected by drugs that disrupt Na+ and lipid homeostasis in malaria parasites

Award Number: R01AI132508

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/05/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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