Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance
Magali Van den Kerkhof, Dorien Mabille, Sarah Hendrickx, Philippe Leprohon, Charles E. Mowbray, Stéphanie Braillard, Marc Ouellette, Louis Maes, Guy Caljon
Abstract
passage in mice and sandflies, suggesting that nonfixed alterations are responsible for the elevated resistance. In line with this, single nucleotide polymorphisms and indels identified by whole-genome sequencing could not be directly linked to the decreased drug susceptibility. Copy number variations were absent, whereas somy changes were detected, which may have accounted for the transient acquisition of resistance. Finally, aminopyrazole activity was not influenced by the MDR and MRP efflux pump inhibitors tested. The selection performed does not suggest the rapid development of resistance against aminopyrazoles in the field. Karyotype changes may confer elevated levels of resistance, but these do not seem to be stable in the vertebrate and invertebrate hosts. MDR/MRP efflux pumps are not likely to significantly impact the activity of the aminopyrazole leads.