Malaria is a devastating global health problem that will become much worse if resistance to frontline antimalarial drugs continues to spread. The loss of effective drug treatment of Plasmodium falciparum, especially the loss of artemisinin (ART) combination therapy (ACT), would be a global public health catastrophe. Recently, polymorphism in a regulatory protein, the Kelch K13-propeller protein was implicated in the loss of efficacy of ART drugs, but the mechanism of resistance is not understood. Understanding the mechanism of ART drug resistance (ART-R) is important for devising ACTs that inhibit further spread of ART-R and for identifying other molecular markers for surveillance and containment programs. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle for better understanding ART-R and for development of new anti-malarial therapeutics. Better knowledge of essential metabolic pathways and vulnerabilities in the parasite's physiologic engine are critical for defining mechanisms of action of existing drugs, how resistance develops to these drugs as well molecular strategies for effective combination therapies. We propose to use a chemogenomic systems approach to define critical pathways linked to ART-R, understand mechanisms of action of ART and other antimalarial partner drugs, and predict drug combination therapies with optimal synergistic anti-parasite activity to minimize the emergence of resistance.

Public Health Relevance

Malaria is a devastating global health problem and its elimination as an important disease requires new therapies. A major hurdle for development of new anti-malarial drugs is a lack of comprehensive information about the best targets. New drugs effective against multiple different targets in malaria parasites are essential to effectivel eliminate malaria. Our project will provide this type of knowledge to improve use of existing drugs and discovery of new drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI117017-04
Application #
9420461
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
O'Neil, Michael T
Project Start
2015-02-10
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of South Florida
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Sá, Juliana M; Kaslow, Sarah R; Krause, Michael A et al. (2018) Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model. Proc Natl Acad Sci U S A 115:12513-12518
Gibbons, Justin; Button-Simons, Katrina A; Adapa, Swamy R et al. (2018) Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum. BMC Genomics 19:849
Zhang, Min; Wang, Chengqi; Otto, Thomas D et al. (2018) Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science 360:
Thomas, Phaedra; Sedillo, Jennifer; Oberstaller, Jenna et al. (2016) Phenotypic Screens Identify Parasite Genetic Factors Associated with Malarial Fever Response in Plasmodium falciparum piggyBac Mutants. mSphere 1:
Cheemalapati, Surya Venkatasekhar; Winskas, John; Wang, Hao et al. (2016) Subcellular and in-vivo Nano-Endoscopy. Sci Rep 6:34400
Wang, Chengqi; Adapa, Swamy R; Gibbons, Justin et al. (2016) Punctuated chromatin states regulate Plasmodium falciparum antigenic variation at the intron and 2 kb upstream regions. BMC Genomics 17:652
Van Voorhis, Wesley C; Adams, John H; Adelfio, Roberto et al. (2016) Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathog 12:e1005763
Pradhan, Anupam; Siwo, Geoffrey H; Singh, Naresh et al. (2015) Chemogenomic profiling of Plasmodium falciparum as a tool to aid antimalarial drug discovery. Sci Rep 5:15930