Dennis Kyle

Chemotherapy and Drug Resistance Research

Research in the Kyle lab focuses on the discovery, development, and mechanism(s) of resistance to anti-parasitic drugs. At present we focus on malaria, the most important parasitic disease of man, and the spectrum of diseases caused by pathogenic free-living amoebae, perhaps the most neglected of all tropical parasitic diseases. The overarching objectives of our research is to develop new tools to prevent disease, to train a new generation of parasitologists, to foster multidisciplinary research on tropical diseases, and to implement our findings to reduce the burden of parasitic diseases in endemic countries.
New drugs are urgently needed to combat malaria, primarily due to the emergence of drug resistance to one or more drugs – a phenomenon known as multidrug resistance. In addition, new drugs are needed that target the dormant hypnozoite stage of vivax malaria that can persist in the liver for weeks to months to years before activating to cause relapsing malaria. With funding from the Bill and Melinda Gates Foundation we have developed a novel system that permits long term maintenance of primary hepatocyte physiology in vitro and have used this technology to develop the first 384 well high content imaging assay to discover anti-hypnozoite drugs.

Elucidating mechanism(s) of resistance and discovering new drug treatment regimens, combinations, or strategies to overcome resistance is a second major research focus. Our studies have demonstrated novel phenotypes that allow P. falciparum to become resistant to artemisinin drugs. In addition, we’ve shown that cryptic mitochondrial heteroplasmy is the mechanism underlying resistance to atovaquone and other drugs that target the mitochondria of P. falciparum.
The pathogenic free-living amoebae Naegleria fowleri and Acanthamoeba spp. cause a spectrum of diseases that have no good treatment options. Primary amoebic meningoencephalitis is an acute fulminating disease caused by N. fowleri and it is >98% fatal within 2 weeks of exposure amoebae in warm freshwater.Acanthamoeba spp cause granulomatous amoebic encephalitis, amoebic keratitis, and skin infections that are equally difficult to treat. The Kyle lab has developed new high throughput methods and assays to discover new drugs that act rapidly, are cidal, and can be combined with existing drugs used to treat these nearly incurable diseases.

Selected Publications

• Duvalsaint M, and Kyle DE. Phytohormones, isoprenoids and role of apicoplast in recovery from dihydroartemisinin-induced dormancy in Plasmodium falciparum. Antimicrobial Agents Chemother. 2018. Jan 8. doi: 10.1128/AAC.01771-17 [Epub ahead of print] PMID: 29311075.
• Thomas SAL, von Salm JL, Clark S, Ferlita S, Neman P, Azhari A, Rice CA, Wilson NG, Kyle DE, and Baker BA. Keikipukalides, furanocembrane diterpenes from the Antarctic deep sea octocoral Plumarella delicatissima. J Nat Prod 2017 Dec 20. doi: 10.1021/acs.jnatprod.7b00732. [Epub ahead of print] PMID: 29260557.
• Neelarpu R, Maignan JR, Lichorowic CL, Monastyrskyi A, Mutka TS, LaCrie AN, Blake LD, Casandra D, Mashkouri S, Burrows JN, Willis PA, Kyle DE, and Manetsch R.Design and synthesis of orally bioavailable piperazine substituted 4(1H)-quinolones with potent antimalarial activity: Structure-activity and structure-property relationship studies. J Med Chem 2017 Dec 7. doi: 10.1021/acs.jmedchem.7b00738. [Epub ahead of print] PMID: 29215279
• Siegel SV, Rivero AV, Oberstaller J, Colon BL, de Buron I, and Kyle DE. Blood flukes Cardicola parvus and C. laruei (Trematoda: Aporocotylidae): life cycles and cryptic infection in spotted seatrout, Cynoscion nebulosus (Telost: Sciaenidae). Parasitol Int 2017 67:150-158. doi: 10.1016/j.parint.2017.10.012. PMID: 29100926
• McQueen A, Blake LD, Azhari A, Kemp MT, McGaha TW Jr, Namelikonda N, Larsen RW, Manetsch R, Kyle DE. Synthesis, characterization, and cellular localization of a fluorescent probe of the antimalarial 8-aminoquinoline primaquine. Bioorg Med Chem Lett 2017 27:4597-4600. doi: 10.1016/j.bmcl.2017.09.030. PMID: 28939120
• Blake LD, Johnson ME, Siegel SV, McQueen A, Iyamu ID, Shaikh AK, Shulktis MW, Manetsch R, Kyle DE. Menoctone resistance in malaria parasites is conferred by M133I mutations in cytochrome b that are transmissible through mosquitos.   Antimicrobial Agents Chemother. 2017 61:e00689-17.https://doi: 10.1128/AAC.00689.17  PMID: 28584157.
• Pradhan A, Siwo G, Singh N, Martens B, Balu B, Button-Simmons K, Tan A, Zhang M, Udenze KO, Jiang RHY, Ferdig MT, Adams JH, Kyle DE. Chemogenomic Profiling of Plasmodium falciparum as a Tool to Aid Antimalarial Drug Discovery.  Sci Reports 2015; 5:15930. doi: 10.1038/srep15930. PMID: 26541648
• Shao CL, Linington RG, Balunas MJ, Centeno A, Boudreau P, Zhang C, Engene N, Spadafora C, Mutka TS, Kyle DE, Gerwick L, Wang CY, Gerwick WH. Bastimolide A, a Potent Antimalarial Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania hirsuta. J Org Chem. 2015; 80(16):7849-55. doi: 10.1021/acs/joc.5b01264. PMID: 26222145.
• Hott A, Tucker MS, Casandra D, Sparks K, Kyle DE. Fitness of Artemisinin-Resistant Plasmodium falciparum in vitro.  J Antimicrob Chemother 2015; 70(10):2787-96. doi: 10.1093/jac/dkv199. PMID: 26203183.
• Baragaña B, Hallyburton I, Lee MC, Norcross NR, Grimaldi R, Otto TD, Proto WR, Blagborough AM, Meister S, Wirjanata G, Ruecker A, Upton LM, Abraham TS, Almeida MJ, Pradhan A, Porzelle A, Martínez MS, Bolscher JM, Woodland A, Norval S, Zuccotto F, Thomas J, Simeons F, Stojanovski L, Osuna-Cabello M, Brock PM, Churcher TS, Sala KA, Zakutansky SE, Jiménez-Díaz MB, Sanz LM, Riley J, Basak R, Campbell M, Avery VM, Sauerwein RW, Dechering KJ, Noviyanti R, Campo B, Frearson JA, Angulo-Barturen I, Ferrer-Bazaga S, Gamo FJ, Wyatt PG, Leroy D, Siegl P, Delves MJ, Kyle DE, Wittlin S, Marfurt J, Price RN, Sinden RE, Winzeler EA, Charman SA, Bebrevska L, Gray DW, Campbell S, Fairlamb AH, Willis PA, Rayner JC, Fidock DA, Read KD, Gilbert IH. A Novel Multiple-Stage Antimalarial Agent that Inhibits Protein Synthesis. Nature. 2015; 522:315-20. 2037-44. doi: 10.1038/nature14451. PMID: 26085270.
• Hott A, Casandra D, Sparks KN, Morton LC, Castanares GG, Rutter A, Kyle DE. Artemisinin-resistant Plasmodium falciparum Exhibit Altered Patterns of Development in Infected Erythrocytes. Antimicrobial Agents Chemother. 2015. 59:3156-67.  doi: 10.1128/AAC.00197-15. PMID: 25779582.
• Rice CA, Colon BL, Alp M, Goker H, Boykin DW, Kyle DE. Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens. Antimicrob Agents Chemother. 2015;59(4):2037-44. doi: 10.1128/AAC.05122-14. PMID: 25605363; PMCID: 4356813.
• María Belén Jiménez-Díaz, Daniel Ebertb, Yandira Salinas, Anupam Pradhan, Adele M. Lehane, Marie-Eve Myrand-Lapierre, Kathleen G. O’Loughlin, David M. Shackleford, Mariana Justino de Almeidai, Angela K. Carrilloc, Julie Clark, Adelaide Dennis, Jonathon Diep, Xiaoyan Deng, Sandra Duffy, Aaron N. Endsley, Greg Fedewa, Armand Guiguemde, Maria G. Gomez-Lorenzo, Gloria Holbrook, Jeremy Horst, Charles C. Kimk, Jian Liul, Marcus C. S. Lee, Amy Matheny, Maria Santos Martínez, Gregory Miller, Ane Rodriguez-Alejandrea, Laura Sanz, Martina Sigal, Natalie Jane Spillman, Philip D. Stein, Zheng Wangl, Fangyi Zhu, David Waterson, Spencer Knapp, Anang Shelat, Vicky M. Avery, David A. Fidock, Francisco-Javier Gamo, Susan A. Charman, Jon C. Mirsalis, Hongshen Ma, Santiago Ferrer, Kiaran Kirk, Iñigo Angulo-Barturen, Dennis E. Kyle, Joseph L. DeRisi, David M. Floyd, and R. Kiplin Guy.  2014.  (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.  PNAS 111: E5455-62. PMID: 25453091.
• Cross RM, Flanigan DL, Monastyrskyi A, LaCrue AN, Saenz FE, Maignan JR, Mutka TS, White KL, Shackleford DM, Bathurst I, Fronczek FR, Wojtas L, Guida WC, Charman SA, Burrows JN, Kyle DE, Manetsch R.  2014.  Orally Bioavailable 6-Chloro-7-methoxy-4(1H)-quinolones Efficacious against Multiple Stages of Plasmodium.  J Med Chem. 57: 8860-8879.  PMID: 2511682.
• Monastyrskyi A, Kyle DE, Manetsch R.  2014.  4(1H)-Pyridone and 4(1H)-Quinolone Derivatives as Antimalarials with Erythrocytic, Exoerythrocytic, and Transmission Blocking Activities.  Curr Top Med Chem. 14: 1693-1705.
• Chen N, LaCrue AN, Teuscher F, Waters NC, Gatton ML, Kyle DE, Cheng Q.  2014.  Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin induced dormant ring stages of Plasmodium falciparum.   Antimicrob Agents Chemother. 58: 4773-4781. PMID: 24913167.
• Maher SP, Crouse RB, Conway AJ, Bannister EC, Achyuta AK, Clark AY, Sinatra FL, Cuiffi JD, Adams JH, Kyle DE, Saadi WM.  2014.  Microphysical space of a liver sinusoid device enables simplified long-term maintenance of chimeric mouse-expanded human hepatocytes.  Biomed Microdevices 16: 727-736. doi: 10.1007/s10544-014-9877-x.
• Henrich PP, O’Brien C, Sáenz FE, Cremers S, Kyle DE, Fidock DA.  2014.  Evidence for pyronaridine as a highly effective partner drug for treatment of artemisinin-resistant malaria in a rodent model.  Antimicrob Agents Chemother. 58(1):183-95.
• Sáenz FE, Lacrue AN, Cross RM, Maignan JR, Udenze KO, Manetsch R, Kyle DE.   2013.  4-(1H)-Quinolones and 1,2,3,4-Tetrahydroacridin-9(10H)-ones prevent the transmission of Plasmodium falciparum to Anopheles freeborni.  Antimicrob Agents Chemotherapy. 57(12):6187-95.
• Nilsen, A., Lacrue, A. N., White, K. L., Forquer, I. P., Cross, R. M., Marfurt, J., Mather, M. W., Delves, M. J., Shackleford, D. M., Saenz, F. E., Morrisey, J. M., Steuten, J., Mutka, T., Li, Y., Wirjanata, G., Ryan, E., Duffy, S., Kelly, J. X., Sebayang, B. F., Zeeman, A. M., Noviyanti, R., Sinden, R. E., Kocken, C. H., Price, R. N., Avery, V. M., Angulo-Barturen, I., Jimenez-Diaz, M. B., Ferrer, S., Herreros, E., Sanz, L. M., Gamo, F. J., Bathurst, I., Burrows, J. N., Siegl, P., Guy, R. K., Winter, R. W., Vaidya, A. B., Charman, S. A., Kyle, D. E., Manetsch, R., and Riscoe, M. K. 2013.  Quinolone-3-diarylethers: a new class of antimalarial drug.  Science Translational Medicine. 5(177):177ra37.
• Cheng Q, Kyle DE, Gatton ML.  2012.  Artemisinin resistance in Plasmodium falciparum: A process linked to dormancy?  Int J Parasitol Drugs Drug Resist. 2:249-255.
• LaCrue AN, Sáenz FE, Cross RM, Udenze KO, Monastyrskyi A, Stein S, Mutka TS, Manetsch R, Kyle DE. 2012.  4(1H)-quinolones with liver stage activity against Plasmodium berghei. Antimicrob Agents Chemother. 57:417-24.
• Srivastava A, Sweat JM, Azizan A, Vesely B, Kyle DE. 2012. Real-time PCR to quantify Lesihmania donovani in hamsters. J Parasitol 99(1): 145-50.
• Balunas MJ, Grosso MF, Villa FA, Engene N, McPhail KL, Tidgewell K, Pineda LM, Gerwick L, Spadafora C, Kyle DE, Gerwick WH. 2012.  Coibacins A-D, Antileishmanial Marine Cyanobacterial Polyketides with Intriguing Biosynthetic Origins. Org Lett. 14(15):3878-3881.
  Sáenz FE, Mutka T, Udenze K, Oduola AM, Kyle DE. 2012.  Novel 4-aminoquinoline analogs highly active against the blood and sexual stages of Plasmodium in vivo and in vitro. Antimicrob Agents Chemother. 56(9): 4685-92.

News

All the pieces matter: UGA researchers collaborate to solve malaria puzzle

Brain-eating amoeba: How do most infections occur? (NewsNation)

Brain-eating amoeba: How do infections occur, and where are they most common? (The Hill)

Increasing the knowledge base on brain-eating amoeba

Trainee Spotlight: Justine Shiau

Researchers implement new tool to screen drugs for treating malaria relapses

UGA researchers developing new models for malaria drug development and testing

Brain-eating amoeba: Where are infections most common, and who is at risk? (Nexstar)

Dennis Kyle Featured Guest on People, Parasites & Plagues Podcast

Dennis Kyle: Finding Solutions for Deadly Diseases

Trainee Spotlight: Alona Botnar

Trainee Spotlight: Emma Troth

Dennis Kyle elected as American Academy of Microbiology Fellow

Banking on Breakthroughs

Dennis Kyle interviewed for Outbreak News Today

Dennis Kyle discusses malaria on WUGA’s Classic City Science

Trainee Spotlight: Beatrice Colon

Scientist of the Week: Dennis Kyle researches malaria to find a cure

Infectious disease expert fights malaria and brain-eating amoeba

Innovation: Expanding the Fight Against Malaria

Three vivax research teams awarded MMV Project of the Year 2016

‘Strong partnership’: UGA’s GRA Eminent Scholars foster innovation and economic development

Noted parasitologist Dennis Kyle named GRA Eminent Scholar at UGA