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      Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series

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          Abstract

          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 (DND i) 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.

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          Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern.

          Phlebotomine sandflies transmit pathogens that affect humans and animals worldwide. We review the roles of phlebotomines in the spreading of leishmaniases, sandfly fever, summer meningitis, vesicular stomatitis, Chandipura virus encephalitis and Carrión's disease. Among over 800 species of sandfly recorded, 98 are proven or suspected vectors of human leishmaniases; these include 42 Phlebotomus species in the Old World and 56 Lutzomyia species in the New World (all: Diptera: Psychodidae). Based on incrimination criteria, we provide an updated list of proven or suspected vector species by endemic country where data are available. Increases in sandfly diffusion and density resulting from increases in breeding sites and blood sources, and the interruption of vector control activities contribute to the spreading of leishmaniasis in the settings of human migration, deforestation, urbanization and conflict. In addition, climatic changes can be expected to affect the density and dispersion of sandflies. Phlebovirus infections and diseases are present in large areas of the Old World, especially in the Mediterranean subregion, in which virus diversity has proven to be higher than initially suspected. Vesiculovirus diseases are important to livestock and humans in the southeastern U.S.A. and Latin America, and represent emerging human threats in parts of India. Carrión's disease, formerly restricted to regions of elevated altitude in Peru, Ecuador and Colombia, has shown recent expansion to non-endemic areas of the Amazon basin. © 2012 The Authors. Medical and Veterinary Entomology © 2012 The Royal Entomological Society.
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            An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site.

            Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by formation of a stable tRNA(Leu)-AN2690 adduct in the editing site of the enzyme. Adduct formation is mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.
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              Mechanism of amphotericin B resistance in clinical isolates of Leishmania donovani.

              The clinical value of amphotericin B, the mainstay therapy for visceral leishmaniasis in sodium antimony gluconate-nonresponsive zones of Bihar, India, is now threatened by the emergence of acquired drug resistance, and a comprehensive understanding of the underlying mechanisms is the need of the hour. We have selected an amphotericin B-resistant clinical isolate which demonstrated 8-fold-higher 50% lethal doses (LD(50)) than an amphotericin B-sensitive strain to explore the mechanism of amphotericin B resistance. Fluorimetric analysis demonstrated lower anisotropy in the motion of the diphenylhexatriene fluorescent probe in the resistant strain, which indicated a higher fluidity of the membrane for the resistant strain than for the sensitive strain. The expression patterns of the two transcripts of S-adenosyl-l-methionine:C-24-Δ-sterol methyltransferase and the absence of ergosterol, replaced by cholesta-5,7,24-trien-3β-ol in the membrane of the resistant parasite, indicate a decreased amphotericin B affinity, which is evidenced by decreased amphotericin B uptake. The expression level of MDR1 is found to be higher in the resistant strain, suggesting a higher rate of efflux of amphotericin B. The resistant parasite also possesses an upregulated tryparedoxin cascade and a more-reduced intracellular thiol level, which helps in better scavenging of reactive oxygen species produced by amphotericin B. The resistance to amphotericin B was partially reverted by the thiol metabolic pathway and ABC transporter inhibitors. Thus, it can be concluded that altered membrane composition, ATP-binding cassette transporters, and an upregulated thiol metabolic pathway have a role in conferring amphotericin B resistance in clinical isolates of Leishmania donovani.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Microorganisms
                Microorganisms
                microorganisms
                Microorganisms
                MDPI
                2076-2607
                29 June 2021
                July 2021
                : 9
                : 7
                : 1408
                Affiliations
                [1 ]Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Wilrijk, Belgium; Magali.Vandenkerkhof@ 123456uantwerpen.be (M.V.d.K.); Dorien.Mabille@ 123456uantwerpen.be (D.M.); sarah.hendrickx@ 123456uantwerpen.be (S.H.); louis.maes@ 123456uantwerpen.be (L.M.)
                [2 ]Centre de Recherche en Infectiologie du Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec City, QC G1V 0A6, Canada; philippe.leprohon@ 123456crchudequebec.ulaval.ca (P.L.); marc.ouellette@ 123456crchudequebec.ulaval.ca (M.O.)
                [3 ]The Wellcome Trust Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK; L.Tulloch@ 123456dundee.ac.uk (L.B.T.); r.z.wall@ 123456dundee.ac.uk (R.J.W.); s.wyllie@ 123456dundee.ac.uk (S.W.)
                [4 ]Drugs for Neglected Diseases initiative (DNDi), 1202 Geneva, Switzerland; echatelain@ 123456dndi.org (E.C.); cmowbray@ 123456dndi.org (C.E.M.); sbraillard@ 123456dndi.org (S.B.)
                Author notes
                [* ]Correspondence: guy.caljon@ 123456uantwerpen.be ; Tel.: +32-32652610
                Author information
                https://orcid.org/0000-0003-3530-0567
                https://orcid.org/0000-0002-2324-9509
                https://orcid.org/0000-0002-4870-3202
                Article
                microorganisms-09-01408
                10.3390/microorganisms9071408
                8305145
                34210040
                f29decf7-9ca6-4513-809a-982ce459970e
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 20 April 2021
                : 24 June 2021
                Categories
                Article

                leishmania,abc transporters,oxaboroles,resistance
                leishmania, abc transporters, oxaboroles, resistance

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