Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance
Current antileishmanial treatment is hampered by limitations, such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases (DND ) has undertaken a drug discovery program, which has...
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Published in | Antimicrobial agents and chemotherapy Vol. 64; no. 9 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Microbiology
20.08.2020
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Subjects | |
Online Access | Get full text |
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Summary: | Current antileishmanial treatment is hampered by limitations, such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases
(DND
) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles, a highly promising antileishmanial chemical series. Multiple experiments have been performed to anticipate the propensity for resistance development. Resistance selection was performed by successive exposure of
promastigotes (
) and intracellular amastigotes (both
and in golden Syrian hamsters). The stability of the resistant phenotypes was assessed after passage in mice and
sandflies. Whole-genome sequencing (WGS) was performed to identify mutated genes, copy number variations (CNVs), and somy changes. The potential role of efflux pumps (the MDR and MRP efflux pumps) in the development of resistance was assessed by coincubation of aminopyrazoles with specific efflux pump inhibitors (verapamil, cyclosporine, and probenecid). Repeated drug exposure of amastigotes did not result in the emergence of drug resistance either
or
Selection at the promastigote stage, however, was able to select for parasites with reduced susceptibility (resistance index, 5.8 to 24.5). This phenotype proved to be unstable after
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Van den Kerkhof M, Mabille D, Hendrickx S, Leprohon P, Mowbray CE, Braillard S, Ouellette M, Maes L, Caljon G. 2020. Antileishmanial aminopyrazoles: studies into mechanisms and stability of experimental drug resistance. Antimicrob Agents Chemother 64:e00152-20. https://doi.org/10.1128/AAC.00152-20. |
ISSN: | 0066-4804 1098-6596 |
DOI: | 10.1128/AAC.00152-20 |