High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.

Bryan T Mott,Tim Mierzwa,Norinne Lacerda-Queiroz,Marc Ferrer,Hongmao Sun,Sam Michael,Monica Kasbekar,Crystal Mcknight,Katy S Sherlach,Amila Siriwardana,Nima Aghdam,Rajarshi Guha,James Inglese,Adam R Renslo,Shaun D Fontaine,Richard T Eastman,Paul Shinn,Dongbo Liu,Paul D Roepe,Jing Yuan,Craig J Thomas,Pwint Khine,Paresma Patel ,Xin‐Zhuan Su ,Lesley Mathews-Griner

doi:10.1038/srep13891

Abstract

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy.

Highlights

Drug resistance in Plasmodium parasites is a constant threat
Other notable findings were the potent activities associated with small molecules targeting human phosphatidylinositide 3-kinases including GSK-2126458 and NVP-BGT226
Our studies indicate that the level of synergy found for antimalarials and ion channel modulators is maintained across the CQ sensitive (CQS) 3D7 and HB3 strains and the CQ resistant (CQR) Dd2 strain (Fig. 2B, Supplementary Fig. 3–5,9)

Summary

Introduction

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. While large-scale single agent screens have identified novel antimalarials, there remains a need for an assessment of new antimalarial drug combinations[10,11]. We performed high-throughput combination screens on compounds with diverse MOAs to identify multiple classes of compounds that interact favorably against P. falciparum

Methods

Results

Conclusion