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Development and Clinical Evaluation of Serum and Urine-Based Lateral Flow Tests for Diagnosis of Human Visceral Leishmaniasis

Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series

Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Wilrijk, Belgium
Centre de Recherche en Infectiologie du Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec City, QC G1V 0A6, Canada
The Wellcome Trust Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Drugs for Neglected Diseases initiative (DNDi), 1202 Geneva, Switzerland
Author to whom correspondence should be addressed.
Academic Editor: María Teresa Gómez-Muñoz
Microorganisms 2021, 9(7), 1408;
Received: 20 April 2021 / Revised: 9 June 2021 / Accepted: 24 June 2021 / Published: 29 June 2021
(This article belongs to the Special Issue Leishmania and Leishmaniasis)
Current treatment options for visceral leishmaniasis have several drawbacks, and clinicians are confronted with an increasing number of treatment failures. To overcome this, the Drugs for Neglected Diseases initiative (DNDi) has invested in the development of novel antileishmanial leads, including a very promising class of oxaboroles. The mode of action/resistance of this series to Leishmania is still unknown and may be important for its further development and implementation. Repeated in vivo drug exposure and an in vitro selection procedure on both extracellular promastigote and intracellular amastigote stages were both unable to select for resistance. The use of specific inhibitors for ABC-transporters could not demonstrate the putative involvement of efflux pumps. Selection experiments and inhibitor studies, therefore, suggest that resistance to oxaboroles may not emerge readily in the field. The selection of a genome-wide cosmid library coupled to next-generation sequencing (Cos-seq) was used to identify resistance determinants and putative targets. This resulted in the identification of a highly enriched cosmid, harboring genes of chromosome 2 that confer a subtly increased resistance to the oxaboroles tested. Moderately enriched cosmids encompassing a region of chromosome 34 contained the cleavage and polyadenylation specificity factor (cpsf) gene, encoding the molecular target of several related benzoxaboroles in other organisms. View Full-Text
Keywords: Leishmania; ABC transporters; oxaboroles; resistance Leishmania; ABC transporters; oxaboroles; resistance
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MDPI and ACS Style

Van den Kerkhof, M.; Leprohon, P.; Mabille, D.; Hendrickx, S.; Tulloch, L.B.; Wall, R.J.; Wyllie, S.; Chatelain, E.; Mowbray, C.E.; Braillard, S.; Ouellette, M.; Maes, L.; Caljon, G. Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series. Microorganisms 2021, 9, 1408.

AMA Style

Van den Kerkhof M, Leprohon P, Mabille D, Hendrickx S, Tulloch LB, Wall RJ, Wyllie S, Chatelain E, Mowbray CE, Braillard S, Ouellette M, Maes L, Caljon G. Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series. Microorganisms. 2021; 9(7):1408.

Chicago/Turabian Style

Van den Kerkhof, Magali, Philippe Leprohon, Dorien Mabille, Sarah Hendrickx, Lindsay B. Tulloch, Richard J. Wall, Susan Wyllie, Eric Chatelain, Charles E. Mowbray, Stéphanie Braillard, Marc Ouellette, Louis Maes, and Guy Caljon. 2021. "Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series" Microorganisms 9, no. 7: 1408.

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