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Alexis Nzila
kilifi [dot] kemri-wellcome [dot] org Research
Molecular parasitology
The control of malaria is hampered by the ability of the parasite to select quickly for resistance against antimalarials. There is no single antimalarial in clinical use against which the parasite has not yet developed resistance. Thus, it is critical to understand mechanisms than underlie the selection and emergence of resistance, this could lead to the discovery of new drugs that are less prone to resistance.
Antifolates are drugs that block the synthesis of folate molecules. Folates are vitamins that are essential for cell multiplication and highly dividing cells, such as cancer cells and malaria parasites rely upon the availability of these vitamins to grow. That is why antifolates are used to treat cancer and malaria. Methotrexate was the first antifolate used in the treatment of cancer.
The most widely used antifolate in the treatment of malaria has been Fansidar, the combination of pyrimethamine/sulfadoxine. This drug is no longer effective in many parts of Africa, including Kenya, due to resistance. Dr Nzila has contributing to the development of simpler ways of tracking and predicting resistance to Fansidar, and helping to better understand the impact of Fansidar on the activity of a new antifolate, known as Lapdap (lapudrine/dapsone). The result of this work has contributed to the development of Lapdap, as an antimalarial. This drug has been phased out because of concern of dapsone toxicity.
Nzila has exploited the vast amount of information from cancer (mammalian cells) research on antifolate and folate biochemistry to better understand malaria folate pathways, so as to identify new targets, therefore discover new drugs against malaria. Using this information, Dr Nzila has discovered a method to increase the efficacy of Fansidar despite the development of resistance, by using an existing drug, probenecid, in combination with Fansidar, and this concept has been tested in human in Nigeria. Dr Nzila has also discovered that some anticancer antifolate drugs such as methotrexate and trimetrexate can be used at low and safe dose to treat malaria. The evaluation of methotrexate as an antimalarial is underway at KEMRI, and a Phase I study on safety and tolerability of low dose of methotrexate has been completed. Experience in cancer research indicates that the malaria parasite has many folate targets, and one of Dr Nzila research topics is to validate these targets.
Antifolate research group
Dr Nzila has also an active research programme on understanding the mechanism of action of non-antifolates drugs such lumefantrine, piperaquine and amodiaquine. This is carried out by association studies between drug activity (in vitro and in vivo) and the whole parasite genome polymorphisms, using high through put sequencing, in collaboration with the Sanger Institute, UK.
Collaborations
Publications
Steven M Kiara, John Okombo, Victor Masseno, Leah Mwai, Isabella Ochola, Steffen Borrmann and Alexis Nzila. In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from Kenyan coast: Emergence of parasites with Ile-164-Leu mutation. Antimicrobial Agent Chem. Jun 15. [Epub ahead of print]
Beatrice Irungu, Daniel Kiboi, Bernard Langat, Geoffrey Rukunga, Sergio Wittlin and Alexis Nzila. Methotrexate and aminopterin lack in vivo antimalarial activity against murine malaria species In press, Experimental Parasitology
Leah Mwai, Edwin Ochong, Abdulrahman Abdi, Stevens Murithi, Steve Ward, Kevin Marsh, Gilbert Kokwaro, Phillip Sassy, Steffen Borrmann and Alexis Nzila. Decrease of chloroquine resistance in Kilifi district, Kenya. Mal J. 2009 8:106.
Victor Masseno, Steven Muriithi and Alexis Nzila. In-vitro chemosensitization of Plasmodim falciparum to antimalarials by verapamil and probenecid. Antimicrobiol Agents Chemother, 2009 53(7): 3131-3132.
Kiboi D.M., B. N. Irungu, B. Langat, S. Wittlin, R. Brun, J.Chollet, O. Abiodun J. K. Nganga, V.C.S. Nyambati, G. M. Rukunga, A. Bell and A. Nzila. Plasmodium berghei ANKA: Selection of resistance to piperaquine and lumefantrine in a mouse model. Experimental Parasitology 2009 22(3):196-202.
Philip Sasi, Abdi Abdulrahaman, Leah Mwai, Judith Straimer, Elise Schieck, Anja Rippert, Mahfudh Bashraheil, Amina Salim, Judith Peshu, Ken Awuondo, Brett Lowe, Munir Pirmohamed, Peter Winstanley, Steve Ward, Alexis Nzila, Steffen Borrmann. In vivo and in vitro efficacy of amodiaquine against Plasmodium falciparum in an area of continued use of 4-aminoquinolines in East Africa. 2009 J Infect Dis. 2009 199:1575-1582
Laura K Certain, Marnie R Briceño, B.A.; Steven M Kiara, Alexis M Nzila, William M Watkins, Carol H Sibley. Limited genetic diversity in pyrimethamine resistant strains of Plasmodium falciparum from Kenya.2008 J Infect Dis. 197(12):1743-51
Eunice Nduati, Abdi Diriye, Ommeth Sheila, Leah Mwai, Steven Kiara, Victor Masseno, Gilbert Kokwaro and Alexis Nzila. Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. Parasitology Research 2008, 102 (6): 1227-1234.
Gilbert Kokwaro, Leah Mwai and Alexis Nzila. Current status of artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. Expert Opin Pharmacother. 2007 Jan;8(1):75-94.
Nzila Alexis. Inhibitors of de novo folate enzymes in Plasmodium falciparum. Drug discovery today, 2006 Oct;11(19-20):939-44.