Harnessing methylotrophs as a bacterial platform to reduce adverse effects of the use of the heavy lanthanide gadolinium in magnetic resonance imaging

Abstract

ABSTRACTGadolinium is a key component of magnetic resonance imaging contrast agents that are critical tools for enhanced detection and diagnosis of tissue and vascular abnormalities. Untargeted post-injection deposition of gadolinium in vivo, and association with diseases like nephrogenic systemic fibrosis, has alerted regulatory agencies to re-evaluate their widespread use and generated calls for safer gadolinium-based contrast agents (GBCAs). Increasing anthropogenic gadolinium in surface water has also raised concerns of potential bioaccumulation in plants and animals. Methylotrophic bacteria can acquire, transport, store and use light lanthanides as part of a cofactor complex with pyrroloquinoline quinone (PQQ), an essential component of XoxF-type methanol dehydrogenases (MDHs), a critical enzyme for methylotrophic growth with methanol. We report robust gadolinium-dependent methanol growth of a genetic variant of Methylorubrum extorquens AM1, named evo-HLn, for “evolved for heavy lanthanides”. Genetic adaptation of evo-HLn resulted in increased xox1 promoter and XoxF MDH activities, transport and storage of Gd3+, and augmented biosynthesis of PQQ. Gadolinium-grown cells exhibited a shorter T1 relaxation time compared to cells with lanthanum or no lanthanide when analyzed by MRI. In addition, evo-HLn was able to grow on methanol using the GBCA Gd-DTPA as the sole gadolinium source, showing the potential of this strain for the development of novel GBCAs and gadolinium recovery from medical waste and/or wastewater.