We work on the identification, heterologous expression, and characterisation of membrane transport proteins (also known as transporters). Transporters control the movement of ions, nutrients, and waste products across the membranes of a cell and are central to its physiology. Proteins of this type also serve as drug targets and/or mediators of drug transport and hence play key roles in the phenomenon of drug resistance.
We are particularly interested in the transporters involved in drug action and drug resistance in the malaria parasite. The malaria parasite is a single-celled microorganism which invades the red blood cells of its host. Malaria remains a major infectious disease in many parts of the world, causing over 200 million cases and around 500,000 deaths per year. Moreover, malaria imposes horrendous economic burdens upon afflicted countries. An effective vaccine remains elusive and reliance on chemotherapy is under serious threat with the emergence of parasites that are resistant to most, if not all, of the current antimalarial drugs.
Our main experimental system is the unfertilised oocyte of the frog Xenopus laevis, in which we express and study transporters from the parasite as well as from a range of other organisms. We complement this system with live parasite assays that indirectly monitor the activity of a transporter within its native environment of the parasite-infected red blood cell.
We use a range of biochemistry, cell physiology, molecular biology, chemistry, and bioinformatic techniques to study:
Transporters of the malaria parasite and of other Apicomplexan parasites, with an emphasis on those involved in drug resistance and drug action
Design and testing of novel antimalarial drugs and antimalarial strategies
Transporters involved in key processes of biomedical, behavioural, or agricultural importance in other organisms, including those encoded by mammals, insects, and plants.
The functions and physiological roles of splice variants of transporters
Zhang V, Kucharski R, Landers C, Richards SN, Bröer S, Martin RE1, and Maleszka R1 (2019). Characterisation of a dopamine transporter and its splice variant reveals novel features of dopaminergic regulation in the honey bee. Frontiers in Physiology, 10: Article 1375. [1: Joint senior authors]
Martin RE (2019). The transportome of the malaria parasite. Biological Reviews, published 07/11/2019.
Martin RE, Shafik SH, and Richards SN (2018). Mechanisms of resistance to the partner drugs of artemisinin in the malaria parasite. Current Opinion in Pharmacology, 42: 71-80.
Bushell E1, Gomes AR1, Sanderson T1, Anar B, Girling G, Herd C, Metcalf T, Modrzynska K, Schwach F, Martin RE, Mather MW, McFadden GI, Parts L, Rutledge GG, Vaidya AB, Wengelnik K, Rayner JC, and Billker O (2017). Functional profiling of a Plasmodium genome reveals an abundance of essential genes. Cell, 170: 260-72. [1: Joint first authors] Open access
Hapuarachchi SV, Cobbold SA1, Shafik SH1, Dennis ASM, McConville MJ, Martin RE, Kirk K, and Lehane AM (2017). The malaria parasite's lactate transporter PfFNT is the target of antiplasmodial compounds identified in whole cell phenotypic screens. PLoS Pathogens, 13: e1006180. [1: Joint second authors] Open access
Richards SN1, Nash MN1, Baker ES, Webster MW, Lehane AM, Shafik SH, and Martin RE (2016). Molecular mechanisms for drug hypersensitivity induced by the malaria parasite's chloroquine resistance transporter. PLOS Pathogens, 12: e1005725. [1: Joint first authors] Open access
Veiga MI1, Dhingra SK1, Henrich PP, Straimer J, Gnadig N, Uhlemann A, Martin RE, Lehane AM, and Fidock DA (2016). Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nature Communications, 7: 11553. [1: Joint first authors] Open access
van Schalkwyk DA1, Nash MN1, Shafik SH1, Summers RL, Lehane AM, Smith PJ, and Martin RE (2015). Verapamil-sensitive transport of quinacrine and methylene blue via the Plasmodium falciparum chloroquine resistance transporter reduces the parasite's susceptibility to these tricyclic drugs. Journal of Infectious Diseases, 213: 800-810. [1: Joint first authors]
Pulcini S, Staines HM, Lee AH, Shafik SH, Bouyer G, Moore CM, Daley DA, Hoke MJ, Altenhofen LM, Painter HJ, Mu J, Llinás M, Ferguson DJP, Martin RE, Fidock DA, Cooper RA, and Krishna S (2015). Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities. Scientific Reports, 5: 14552. Open access
Marchetti RV, Lehane AM, Shafik SH, Winterberg M, Martin RE, and Kirk K (2015). A lactate and formate transporter in the intraerythrocytic malaria parasite, Plasmodium falciparum. Nature Communications, 6: Article 6721. Open access
Bellanca S, Summers RL, Meyrath M, Dave A, Nash MN, Dittmer M, Sanchez CP, Stein WD, Martin RE1, and Lanzer M1 (2014). Multiple drugs compete for transport via the P. falciparum chloroquine resistance transporter at distinct but interdependent sites. Journal of Biological Chemistry, 289: 36336-51. [1: Joint senior authors] Open access
Teng R1, Lehane AM1, Winterberg M, Shafik SH, Summers RL, Martin RE, van Schalkwyk DA, Junankar PR, and Kirk K (2014). 1H NMR metabolite profiles of different strains of Plasmodium falciparum. Bioscience Reports, 34: art:e00150. [1: Joint first authors] Open access
Summers RL1, Dave A1, Dolstra TJ, Bellanca S, Marchetti RV, Nash MN, Richards SN, Goh V, Schenk RL, Stein WD, Kirk K, Sanchez CP, Lanzer M2, and Martin RE2 (2014). Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter. Proceedings of the National Academy of Sciences USA, 111: E1759-67. [1, 2: Equal contributions] Open access
Deane KJ1, Summers RL1, Lehane AM, Martin RE2, and Barrow RA2 (2014). Chlorpheniramine analogues reverse chloroquine resistance in Plasmodium falciparum by inhibiting PfCRT. ACS Medicinal Chemistry Letters, 5: 576-81 [1, 2: Equal contributions]
Hrycyna CA1, Summers RL1, Lehane AM1, Pires MM, Namanja H, Bohn K, Kuriakose J, Ferdig M, Henrich PP, Fidock DA, Kirk K, Chmielewski J2, and Martin RE2 (2013). Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum. ACS Chemical Biology, 9:722-30 [1, 2: Equal contributions] Open access
Gemma S, Camodeca C, Brindisi M, Brogi S, Kukreja G, Kunjir S, Gabellieri E, Lucantoni L, Habluetzel A, Taramelli D, Basilico N, Gualdani R, Tadini-Buoninsegni F, Bartolommei G, Moncelli MR, Martin RE, Summers RL, Lamponi S, Savini L, Fiorini I, Valoti M, Novellino E, Campiani G, and Butini S (2012). Mimicking the intramolecular hydrogen Bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents. Journal of Medicinal Chemistry, 55: 10387-10404.
Gemma S, Camodeca C, Sanna Coccone S, Joshi BP, Bernetti M, Moretti V, Brogi S, Bonache MC, Savini L, Taramelli D, Basilico N, Parapini S, Rottmann M, Brun R, Lamponi S, Caccia S, Guiso G, Summers RL, Martin RE, Saponara S, Gorelli B, Novellino E, Campiani G, and Butini S (2012). Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: further structure-activity relationships, in vivo studies, and preliminary toxicity profiling. Journal of Medicinal Chemistry, 55: 6948-67.
Martin RE, Butterworth A, Gardiner D, Kirk K, McCarthy JS, and Skinner-Adams TS (2012). Saquinavir inhibits the malaria parasite's chloroquine resistance transporter. Antimicrobial Agents and Chemotherapy, 56: 2283-9. Open access
Summers, RL, Nash MN, and Martin RE (2012). Know your enemy: Understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics. Cellular and Molecular Life Sciences, 69, 1967-95.
Zishiri VK, Joshi MC, Hunter R, Chibale K, Smith PJ, Summers RL, Martin RE, and Egan TJ (2011). Quinoline antimalarials containing a dibemethin group are active against chloroquine-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine resistance transporter. Journal of Medicinal Chemistry, 54, 6956-68.
Zishiri VK, Hunter R, Smith PJ, Taylor D, Summers RL, Kirk K, Martin RE, and Egan TJ (2011). A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT. European Journal of Medicinal Chemistry, 46: 1729-42.
Cobbold SA, Martin RE, and Kirk K (2011). Methionine transport in the malaria parasite, Plasmodium falciparum. International Journal of Parasitology, 41: 125-135.
Summers, RL and Martin RE (2010). Functional characteristics of the malaria parasite’s ‘chloroquine resistance transporter’: implications for chemotherapy. Virulence, 1, 304-08. Open access
Martin RE, Ginsburg H and Kirk K (2009). Membrane transport proteins of the malaria parasite. Molecular Microbiology, 74: 519-528.
Martin RE, Marchetti RV, Cowan AI, Howitt SM, Bröer S, and Kirk K (2009). Chloroquine transport via the malaria parasite’s ‘Chloroquine Resistance Transporter’. Science, 325, 1680-82. Commentaries: (i) Nelson, N (2009) Faculty of 1000, article 1165434a, (ii) Sibley, LD (2009) Faculty of 1000, article 1165434b, and (iii) This week in Science (2009) Science, 325: 1596-7.
Henry RI, Martin RE, Howitt SM, and Kirk K (2007). Localisation of a candidate anion transporter to the surface of the malaria parasite. Biochem. Biophys. Res. Comm. 363: 288-291.
Saliba KJ1, Martin RE1, Bröer A, Henry RI, McCarthy CS, Downie MJ, Allen RJW, Mullin KA, McFadden GI, Bröer S2, and Kirk K2 (2006). Na+-dependent uptake of an essential nutrient by the intracellular malaria parasite. Nature,443: 582-85. [1, 2: Equal contributions] Commentary: Merzendorfer H. (2007) J Exp Biol, 210: v-vi.
Bray PG1, Martin RE1, Tilley L, Ward SA, Kirk K, and Fidock DA (2005). Defining the role of PfCRT in P. falciparum chloroquine resistance. Molecular Microbiology, 56: 323-33. [1: Joint first authors]
Martin RE, Henry RI, Abbey JL, Clements JD, and Kirk K (2005). The ‘permeome’ of the malaria parasite: an overview of the membrane transport proteins of Plasmodium falciparum. Genome Biology, 6: R26. Open access
Kirk K, Martin RE, Bröer S, Howitt SM, and Saliba KJ (2005). Plasmodium Permeomics: Membrane transport proteins in the malaria parasite. Current Topics in Microbiology and Immunology: Malaria (S. Krishna and D. Sullivan, eds), 295: 325-356.
Martin RE and Kirk K (2004). The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Molecular Biology and Evolution, 21: 1938-49. Commentaries: (i) Egan TJ. (2004) Drug Discovery Today, 9: 814-815 and (ii) Hughes A. (2004) Faculty of 1000, article 15240840
Clements JD and Martin RE (2002). Identification of novel membrane proteins by searching for patterns in hydropathy profiles. FEBS Journal, 269: 2101-07.
Saliba KJ, Martin RE, Staines HM, and Kirk K (1999). A novel anion channel in the malaria-infected erythrocyte: opportunities for antimalarial chemotherapy, in Chloride Channels (RZ Kozlowski, ed), Isis Medical Media, pp 137‐48.
Kirk K, Staines HM, Martin RE, and Saliba KJ (1999). Transport properties of the host cell membrane, in transport and trafficking in the malaria‐infected rrythrocyte, Wiley, Chichester (Novartis Foundation Symposium 226), pp 55‐73.
The genome of the malaria parasite Plasmodium falciparum is maintained primarily as transcriptionally competent, euchromatin with only rest
A key mediator of protective immunity to malaria is antibodies that block merozoite invasion of the RBC.
Mechanosensitive channels are fundamental molecular components of mechanosensory systems in all organisms.
DNA is the target biomolecule of many anticancer drugs because DNA replication is one of the most vulnerable cellular process.
Voltage-gated sodium channels are integral in electrical signaling within the human body and are key targets for anesthetics and antiepileptic comp
The mitotic spindle is a large molecular machine that controls chromosome segregation and cytokinesis in animal and plant cells.