Person: Magistrado, Pamela
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Publication Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
(Nature Pub. Group, 2015) Hameed P., Shahul; Solapure, Suresh; Patil, Vikas; Henrich, Philipp P.; Magistrado, Pamela; Bharath, Sowmya; Murugan, Kannan; Viswanath, Pavithra; Puttur, Jayashree; Srivastava, Abhishek; Bellale, Eknath; Panduga, Vijender; Shanbag, Gajanan; Awasthy, Disha; Landge, Sudhir; Morayya, Sapna; Koushik, Krishna; Saralaya, Ramanatha; Raichurkar, Anandkumar; Rautela, Nikhil; Roy Choudhury, Nilanjana; Ambady, Anisha; Nandishaiah, Radha; Reddy, Jitendar; Prabhakar, K. R.; Menasinakai, Sreenivasaiah; Rudrapatna, Suresh; Chatterji, Monalisa; Jiménez-Díaz, María Belén; Martínez, María Santos; Sanz, Laura María; Coburn-Flynn, Olivia; Fidock, David A.; Lukens, Amanda; Wirth, Dyann; Bandodkar, Balachandra; Mukherjee, Kakoli; McLaughlin, Robert E.; Waterson, David; Rosenbrier-Ribeiro, Lyn; Hickling, Kevin; Balasubramanian, V.; Warner, Peter; Hosagrahara, Vinayak; Dudley, Adam; Iyer, Pravin S.; Narayanan, Shridhar; Kavanagh, Stefan; Sambandamurthy, Vasan K.The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg−1 and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4–5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.
Publication A broad analysis of resistance development in the malaria parasite
(Nature Publishing Group, 2016) Corey, Victoria C.; Lukens, Amanda; Istvan, Eva S.; Lee, Marcus C. S.; Franco, Virginia; Magistrado, Pamela; Coburn-Flynn, Olivia; Sakata-Kato, Tomoyo; Fuchs, Olivia; Gnädig, Nina F.; Goldgof, Greg; Linares, Maria; Gomez-Lorenzo, Maria G.; De Cózar, Cristina; Lafuente-Monasterio, Maria Jose; Prats, Sara; Meister, Stephan; Tanaseichuk, Olga; Wree, Melanie; Zhou, Yingyao; Willis, Paul A.; Gamo, Francisco-Javier; Goldberg, Daniel E.; Fidock, David A.; Wirth, Dyann; Winzeler, Elizabeth A.Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.