Mystery of the Adaptive Proline Response Solved
Our previous studies identified a unique mechanism of resistance to halofuginone (HFG), a Plasmodium falciparum prolyl tRNA synthetase inhibitor (PfProRS), via increased intraparasitic proline levels which we termed the Adaptive Proline Response (APR). The molecular mechanisms underlying the APR remained a mystery until the current study. We demonstrate that the increased proline largely derives from arginine; however, further experiments revealed that the arginine to proline pathway was not essential for the APR. After discovering mutations in the P. falciparum Apicomplexan amino acid transporter 2 (PfApiAT2), we show that loss of function of PfApiAT2 is the primary molecular determinant of the APR. This is a novel mode of resistance for P. falciparum and has implications for drug development.