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proteomic approaches for discovery of new targets for vaccine and therapeutics against visceral leishmaniasis.visceral leishmaniasis (vl) is the most devastating type caused by leishmania donovani, leishmania infantum, and leishmania chagasi. the therapeutic mainstay is still based on the antiquated pentavalent antimonial against which resistance is now increasing. unfortunately, due to the digenetic life cycle of parasite, there is significant antigenic diversity. there is an urgent need to develop novel drug/vaccine targets against vl for which the primary goal should be to identify and characterize t ...200821136840
dual culture method to determine the relationship of gut bacteria of sandfly (phlebotomus argentipes) with promastigotes of leishmania donovani.a simple dual culture agar plating technique has been developed and evaluated for its efficiency in determining the relationship of gut bacteria of sandfly with leishmania donovani promastigotes. there are about twenty morphologically distinct bacterial colonies have been isolated from the gut homogenate of phlebotomus argentipes. in dual culture method, each bacterial isolate was inoculated in one half of the plate and the promastigotes of leishmania was inculcated in the other half by streakin ...200819301698
synthesis and antiprotozoal activities of simplified analogs of naphthylisoquinoline alkaloids.the naphthylisoquinoline alkaloids (niqs) represent a class of natural products with manifold activities against various tropical diseases. they are isolated from rare and difficult-to-cultivate tropical plants. in order to find novel, more easily accessible analogs and to study structure-activity relationships, a variety of simplified analogs were produced, which bear the functional groups typical of the niqs, but avoid the synthetically difficult elements of chirality, stereogenic centers and ...200817475370
sequence elements essential for the rapid turnover of crithidia fasciculata ornithine decarboxylase.ornithine decarboxylase (odc) has a very fast turnover in mammalian cells, but is a stable enzyme in t. brucei and other trypanosmatid parasites like leishmania donovani. however, crithidia fasciculata, which is a phylogenetically closely related trypanosomatid to l. donovani, has an odc with a rapid turnover. interestingly, c. fasciculata odc, but not l. donovani odc, is rapidly degraded also in mammalian systems. in order to obtain information on what sequences are important for the rapid degr ...200817514492
trafficking of leishmania donovani promastigotes in non-lytic compartments in neutrophils enables the subsequent transfer of parasites to macrophages.inoculation of leishmania (l.) spp. promastigotes in the dermis of mammals by blood-feeding sand flies can be accompanied by the rapid recruitment of neutrophils, inflammatory monocytes and dendritic cells. despite the presence of these lytic leucocytes, parasitism is efficiently established. we show here that leishmania donovani promastigotes are targeted to two different compartments in neutrophils. the compartments harbouring either damaged or non-damaged parasites were characterized at the e ...200817651446
erythrocyte glutathione status in human visceral leishmaniasis.a glutathione redox cycle is a major antioxidant defense system for the detoxification of reactive oxygen species within erythrocytes. reactive oxygen species such as superoxide anions, hydrogen peroxide and hydroxyl radicals are generated as a host defense mechanism for killing of engulfed leishmania donovani, a causative agent of visceral leishmaniasis, are capable of damaging lipids and other biomolecules when produced in excess. erythrocytes are most vulnerable to reactive oxygen species. in ...200823105731
induction of apoptosis-like cell death by pentamidine and doxorubicin through differential inhibition of topoisomerase ii in arsenite-resistant l. donovani.the current study has been undertaken to investigate the sensitivity of the topoisomerase ii (topo ii) of wild type (ld-wt) and arsenite-resistant (ld-as20) l. donovani to an anti-leishmanial agent pentamidine and an anti-cancer drug doxorubicin. we demonstrate that the cross resistance to pentamidine and doxorubicin in ld-as20, was in part implicated through differential inhibition of topo ii in ld-wt and ld-as20. further, the treatment of promastigotes at drug concentrations inhibiting 50% of ...200717655815
leishmanial antigens in liposomes promote protective immunity and provide immunotherapy against visceral leishmaniasis via polarized th1 response.leishmaniasis affects 12 million people, and it is generally agreed that vaccination provides the best long-term strategy for its control. an ideal vaccine should be effective in both preventing and treating leishmaniasis. however, immunological correlates to predict vaccine efficacy and success of treatment in visceral leishmaniasis (vl) remain ill defined. here, we correlated the vaccine efficacy of soluble leishmanial antigens (sla) from leishmania donovani promastigote membrane, entrapped in ...200717655984
amphotericin b treatment for indian visceral leishmaniasis: response to 15 daily versus alternate-day infusions.for patients with indian visceral leishmaniasis, amphotericin b deoxycholate is usually given as 15 alternate-day infusions of 1 mg/kg over 30 days (total dose, 15 mg/kg); daily treatment with 1 mg/kg for 20 days (total dose, 20 mg/kg) is also used. this study was done to address the unsettled therapeutic questions of administration schedule (alternate-day vs. daily administration) and dose (1 vs. 0.75 mg/kg) and to determine whether the duration of amphotericin b treatment in bihar, india, can ...200717682988
interleukin-10 and the pathogenesis of human visceral leishmaniasis.the mechanisms underlying the failure to control the growth and systemic spread of leishmania parasites in human visceral leishmaniasis (vl) are not well understood. although the absence of antigen-specific th1 responses in the peripheral blood mononuclear cells from vl patients is thought to be causally related to disease progression, the finding that these patients also express elevated interferon-gamma mrna in lesional tissue, as well as elevated serum levels of proinflammatory cytokines, sug ...200717689290
in vitro activity of 10-deacetylbaccatin iii against leishmania donovani promastigotes and intracellular amastigotes.current treatments for leishmaniasis are unsatisfactory due to their route of administration, toxicity and expense but, most importantly, to the developed resistance of leishmania to first-line drugs. therefore, the identification of new effective targeted drugs is an urgent need. since many studies have shown that medicinal plants contain compounds active against protozoa we have undertaken a study aiming to determine the antileishmanial activity of the taxoid 10-deacetylbaccatin iii, isolated ...200717691059
2,n6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities.a library of 2,n(6)-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. it was found that 2-methoxy and 2-histamino and n(6)-m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. the best antiplasmodial activity was achieved with large aromatic substitutions, such as n(6)-2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the ...200717698622
phlebotomus (euphlebotomus) mascomai n. sp. (diptera-psychodidae).a new species of sandfly is described from limestone caves in thailand. the inclusion of this species in the subgenus euphlebotomus is justified on the basis of characters of the male genitalia (paramere, basal lobe). the male-female gathering in the same taxon is based on ecological (cavernicolous species), morphological (length of male genital filaments and female spermathecal ducts) and molecular (homology of cytochrome b mt dna sequences) criteria. a differential diagnosis between phlebotomu ...200717710436
cutaneous pseudolymphoma in association with leishmania donovani. 200717714564
in vivo studies on the antileishmanial activity of buparvaquone and its prodrugs.the efficacy of different formulations of the naphthoquinone buparvaquone and two phosphate prodrugs in in vivo models of both visceral and cutaneous leishmaniasis is described.200717715126
characterization of metacaspases with trypsin-like activity and their putative role in programmed cell death in the protozoan parasite leishmania.in this report, we have characterized two metacaspases of leishmania donovani, l. donovani metacaspase-1 (ldmc1) and ldmc2. these two proteins show 98% homology with each other, and both contain a characteristic c-terminal proline-rich domain. both genes are transcribed in promastigotes and axenic amastigotes of l. donovani; however, ldmc1 shows increased mrna levels in axenic amastigotes. an anti-ldmc antibody was obtained and showed reactivity with a single approximately 42-kda protein band in ...200717715367
in vitro activity of an essential oil against leishmania donovani.the in vitro antileishmanial effect of the essential oil from chenopodium ambrosioides against leishmania donovani was investigated. the product showed significant activity against promastigotes and amastigotes, with a 50% effective concentration of 4.45 and 5.1 microg/ml, respectively. the essential oil caused an irreversible inhibition of the growth of promastigotes after a treatment with 100 or 10 microg/ml for 1 or 24 h, respectively. the phagocytic activity of the macrophages was preserved ...200717724767
first detection and genetic typing of leishmania infantum mon-24 in a dog from the moroccan mediterranean coast: genetic diversity of mon-24.as in the countries edging the mediterranean basin, leishmania infantum zymodeme mon-1 is the main causative agent of visceral leishmaniasis in morocco, where visceral leishmaniasis is most active in the north-eastern slopes of the rif mountains. the dog was confirmed to be the main reservoir of l. infantum mon-1, while the reservoir of l. infantum mon-24 causative agent of both infantile visceral leishmaniasis and cutaneous leishmaniasis has not yet been identified. here we report the first det ...200717603990
visceral leishmaniasis: a threat to immunocompromised patients in non-endemic areas?visceral leishmaniasis is rare in western europe, but may be life-threatening in immunocompromised patients. it is therefore important to understand the incidence of the disease in a non-endemic area and its relationship with immunosuppressive conditions. between 1990 and 2005, 12 patients were diagnosed with leishmaniasis at basel university hospital, switzerland. eleven presented with visceral symptoms and ten had an underlying immunosuppressive condition. since increasing numbers of immunosup ...200717610597
increased levels of thiols protect antimony unresponsive leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony.the current trend of antimony (sb) unresponsiveness in the indian subcontinent is a major impediment to effective chemotherapy of visceral leishmaniasis (vl). although contributory mechanisms studied in laboratory-raised sb-r parasites include an up-regulation of drug efflux pumps and increased thiols, their role in clinical isolates is not yet substantiated. accordingly, our objectives were to study the contributory role of thiols in the generation of sb unresponsiveness in clinical isolates. p ...200717612420
antileishmanial efficacy of amphotericin b bearing emulsomes against experimental visceral leishmaniasis.amphotericin b (amb) was formulated in trilaurin-based emulsomes (nanosize lipid particles) stabilized by soya phosphatidylcholine (pc), as a new delivery system for macrophage targeting for the treatment of visceral leishmaniasis (vl). emulsomes were modified by coating them with macrophage-specific ligand (o-palmitoyl mannan, opm). the antileishmanial activity of amb-deoxycholate (amb-doc) and emulsome entrapped amb was tested in vitro in leishmania donovani infected macrophage-amastigote syst ...200717613662
synthesis, biological evaluation, and molecular modeling of 3,5-substituted-n1-phenyl-n4,n4-di-n-butylsulfanilamides as antikinetoplastid antimicrotubule agents.dinitroanilines are of interest as antiprotozoal lead compounds because of their selective activity against the tubulin of these organisms, but concern has been raised due to the potentially mutagenic nitro groups. analogues of n(1)-phenyl-3,5-dinitro-n(4),n(4)-di-n-butylsulfanilamide (gb-ii-150, compound 2b), a selective antimitotic agent against african trypanosomes and leishmania, have been prepared where the nitro groups are replaced with amino, chloro, cyano, carboxylate, methyl ester, amid ...200717618122
first case of indigenous visceral leishmaniasis from central india.visceral leishmaniasis is endemic in the eastern states of india, but central india remains free of leishmaniais. this report describes the first indigenous case of visceral leishmaniasis in a seven-year-old girl from central india. the child presented with fever for 10 days and was diagnosed by bone marrow examination, serology using rke16 and rk39 antigens, and a polymerase chain reaction specific for the kinesin gene. sequencing of the immunodominant region of the kinesin gene of the parasite ...200717620636
comparison of conventional methods for diagnosis of visceral leishmaniasis in children of the center-west region of brazil.in brazil, sophisticated techniques currently employed for diagnosis of visceral leishmaniasis, such as polymerase chain reaction-based assays, are only available in major research centers, whereas conventional methods are still used in many areas where the disease occurs. in the state of mato grosso do sul, in the country's center-west region, visceral leishmaniasis has recently emerged in many cities, and duration of the disease, from the onset of symptoms to diagnosis, has been short. conside ...200717625737
visceral leishmaniasis diagnosed on duodenal biopsy. 200717628327
inactivation of the miltefosine transporter, ldmt, causes miltefosine resistance that is conferred to the amastigote stage of leishmania donovani and persists in vivo.miltefosine (hexadecylphosphocholine) is the first oral antileishmanial drug. in this study, we addressed the question whether miltefosine-resistant leishmania donovani promastigotes transform to miltefosine-resistant amastigotes. a promastigote line, m-mutr, showed defective internalisation of miltefosine owing to mutations in ldmt, similar to previously described resistant lines. m-mutr parasites were infective to macrophages in vitro as well as in balb/c mice in vivo. there was good correlati ...200717628445
evolutionary and geographical history of the leishmania donovani complex with a revision of current taxonomy.leishmaniasis is a geographically widespread severe disease, with an increasing incidence of two million cases per year and 350 million people from 88 countries at risk. the causative agents are species of leishmania, a protozoan flagellate. visceral leishmaniasis, the most severe form of the disease, lethal if untreated, is caused by species of the leishmania donovani complex. these species are morphologically indistinguishable but have been identified by molecular methods, predominantly multil ...200717517634
the utility of exoantigens for detection of leishmania infections.exoantigens released by leishmania promastigotes were the subject of a workshop held in mombasa, kenya. investigators from the walter reed army institute of research (silver spring, maryland) met with scientists from government and academic institutes and industry to review the current global status of leishmaniasis and to explore the potential role of exoantigens in the detection of leishmania in the vertebrate host and arthropod vector. some encouraging data, particularly in the immunodiagnosi ...200717521094
leishmania donovani iron superoxide dismutase a is targeted to the mitochondria by its n-terminal positively charged amino acids.many reports have shown that leishmania species are susceptible to reactive oxygen species (ros) and reactive nitrogen species (rns)-mediated killing. the superoxide dismutase (sod) is one of the antioxidant defense enzymes important for parasite survival through its detoxification of superoxide into hydrogen peroxide and oxygen. the mitochondria produce numerous superoxide radicals as a by-product of cellular respiration and hence targeting of sods to the mitochondria is critical in maintaining ...200717524502
synthesis and in vitro protozoocidal activity of diazabicyclic benzotropolone derivatives.we describe the synthesis and protozoocidal evaluation of a series of diazabicycles based on benzotropolone ethers. several of the compounds, which can be obtained through a high-yielding hetero diels-alder reaction using simple and readily available starting materials, have in vitro activities against trypanosoma cruzi and leishmania donovani that are comparable to, and in some cases better than, those of currently used chemotherapies.200717532634
autochthonous visceral leishmaniasis: a report of a second case in thailand.visceral leishmaniasis (vl) is a rare disease in thailand. only one previous case has been reported in which transmission was likely autochthonous. we conducted an investigation of a case of vl, which included serological and symptom surveys of people who lived near the case in nan province and bangkok, serological surveys of domestic animals in his home village and sand fly surveys in his home village and in bangkok. no humans interviewed met our case definition for possible vl. one hundred thi ...200717539239
leishmania donovani and cutaneous leishmaniasis, sri lanka.to investigate the relationship of cutaneous leishmaniasis isolates from sri lanka to known species, we performed dna sequencing and microsatellite analyses. we identified leishmania donovani as the agent of sri lanka cutaneous leishmaniasis and showed that these parasites are closely related to those causing visceral leishmaniasis in the indian subcontinent.200717552105
kala-azar control, uganda. 200717552117
amino acid residues of leishmania donovani cyclophilin key to interaction with its adenosine kinase: biological implications.cyclophilins (cyps), by interacting with a variety of proteins, often modulate their biological activities and thus have been implicated in several cellular functions. however, mechanisms that determine such interactions are poorly understood. we earlier reported that an endoplasmic reticulum (er)-located cyclophilin (ldcyp) from the purine auxotrophic parasitic protozoan leishmania donovani reactivated its adenosine kinase (adk). the adk-reactivating property of ldcyp was however abolished at h ...200717552497
transcriptome analysis during the process of in vitro differentiation of leishmania donovani using genomic microarrays.leishmania donovani causes visceral disease (kala-azar), a major health problem throughout the tropics with 500 000 new cases every year. leishmania differentiates from the promastigote to the amastigote form to establish infection in a mammalian host. to understand the process of differentiation, we assessed the global variation in gene expression in promastigotes, an intermediate stage of differentiation (pa24) and axenic amastigotes in culture using an l. donovani genomic microarray with 4224 ...200717553180
mrna cycling sequence binding protein from leishmania donovani (ldcsbp) is covalently modified by ubiquitination.the lack of transcriptional regulation in trypanosomatids suggests the presence of distinct posttranscriptional mechanisms to control differential gene expression. in fact, the stability of s-phase specific mrnas in these parasites is determined primarily by the presence of the octanucleotide sequence (c/a)auagaa(g/a) in the utrs of the transcripts. here, the characterization of ldcsbp is reported, which specifically binds to the octanucleotide containing rna. the ldcsbp protein contains multipl ...200717559572
a computational docking study for prediction of binding mode of diospyrin and derivatives: inhibitors of human and leishmanial dna topoisomerase-i.a computational approach was utilized to study the relative binding modes of diospyrin (bisnaphthoquinonoid) with the crystal structure of human dna-topoi and the recently reported leishmania donavani dna-topoi. additionally, the binding site interactions of amino derivatives of diospyrin with human topoi were studied extensively. based on the docking results, binding modes of diospyrin with the human and leishmanial topoi catalytic core were predicted. the parallel use of two efficient and pred ...200717562360
visceral leishmaniasis after allogeneic hematopoietic stem cell transplantation. 200717572716
injectable paromomycin for visceral leishmaniasis in india.visceral leishmaniasis (kala-azar) affects large, rural, resource-poor populations in south asia, africa, and brazil. safe, effective, and affordable new therapies are needed. we conducted a randomized, controlled, phase 3 open-label study comparing paromomycin, an aminoglycoside, with amphotericin b, the present standard of care in bihar, india.200717582067
tamoxifen is effective against leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring leishmania (leishmania) amazonensis amastigotes.this study was performed to investigate the activity of tamoxifen, an antioestrogen widely used in the treatment of breast cancer, against leishmania.200717584801
locally acquired visceral leishmaniasis in sri lanka. 200717585579
over-expression of leishmania major map kinases reveals stage-specific induction of phosphotransferase activity.during the infectious cycle, protozoan parasites undergo various developmental transitions and switch virulence factors in response to extracellular signals in insect vectors and human hosts. despite the importance of environmental sensing in parasite pathogenicity, little is known about the pathways that transduce extracellular signals into stage-specific gene expression. here, we used a transgenic approach to gain insight into localisation and activity of three green fluorescence protein (gfp) ...200717481635
age-influenced population kinetics and immunological responses of leishmania donovani in hamsters.susceptibility of animals to infections depends upon various factors including sex and age of the host, which plays a pivotal role. in this communication, we have investigated the "intake" of leishmania donovani infection in young (3-4 weeks old) and adult (15-16 weeks old) golden hamsters. the splenic parasite load in young hamsters on day 15 post infection (p.i.) was 54 +/- 4 amastigotes/100 macrophage nuclei and increased to 106.3 +/- 3.5 on day 30 p.i. however, adult group showed 2.2-(p < 0. ...200717484071
cutaneous leishmaniasis caused by leishmania tropica in bikaner, india: parasite identification and characterization using molecular and immunologic tools.identification of new foci of cutaneous leishmaniasis (cl), along with reports of leishmania donovani causing the disease, is an issue of concern. clinico-epidemiologic analysis of 98 cases in the endemic regions of rajasthan state, india, suggested the preponderance of infection in men (62.24%) compared with women (37.75%). species characterization by internal transcribed spacer 1 (its1) polymerase chain reaction (pcr)-restriction fragment length polymorphism (rflp), kdna-pcr, and immunofluores ...200717488912
short report: production of recombinant kinesin-related protein of leishmania donovani and its application in the serodiagnosis of visceral leishmaniasis.to detect igg antibody in the serodiagnosis of visceral leishmaniasis (vl), a recombinant antigen rk39, which is part of a leishmania chagasi kinesin-related protein, has been used successfully and showed high sensitivity and specificity. we report production of a recombinant protein rkrp42, which is part of an l. donovani kinesin-related protein and a homolog of rk39, and its application in an enzyme-linked immunosorbent assay (elisa) for the diagnosis of vl. when rkrp42 and rk39 were compared, ...200717488913
y chromosome lineage- and village-specific genes on chromosomes 1p22 and 6q27 control visceral leishmaniasis in sudan.familial clustering and ethnic differences suggest that visceral leishmaniasis caused by leishmania donovani is under genetic control. a recent genome scan provided evidence for a major susceptibility gene on chromosome 22q12 in the aringa ethnic group in sudan. we now report a genome-wide scan using 69 families with 173 affected relatives from two villages occupied by the related masalit ethnic group. a primary ten-centimorgan scan followed by refined mapping provided evidence for major loci at ...200717500593
[treatment of visceral leishmaniasis in children].visceral leishmania infantum leishmaniasis is endemic in the south of france. for many years the mainstay for treatment of infected children was pentavalent antimony: meglumine antimoniate (glucantime) or sodium stibogluconate (pentostam). however these drugs are poorly tolerated and resistance similar to that observed in the treatment of indian visceral leishmania donovani leishmaniasis has been reported. currently liposomal amphotericin b is being used instead of antimony for treatment of visc ...200717506279
leishmania donovani: inhibition of phagosomal maturation is rescued by nitric oxide in macrophages.leishmania donovani promastigotes, the causative agent of visceral leishmaniasis, survive inside macrophages by inhibiting phagosomal maturation. the main surface glycoconjugate on promastigotes, lipophosphoglycan (lpg), is crucial for parasite survival. lpg has several detrimental effects on macrophage function, including inhibition of periphagosomal filamentous actin (f-actin) breakdown during phagosomal maturation. however, in raw 264.7 macrophages pre-stimulated with lipopolysaccharide (lps) ...200717511987
safety trial using the leishmune vaccine against canine visceral leishmaniasis in brazil.a group of 600 healthy and asymptomatic dogs from brazilian canine visceral leishmaniasis endemic areas was vaccinated with three sc doses of leishmune which is the industrialized formulation of the fml-saponin, recently licensed for commercialization in brazil, which previously showed 76-80% vaccine efficacy against canine visceral leishmaniasis. safety evaluation was performed for 14 days after each vaccine injection and disclosed transient reactions of local pain (40.87%), anorexia (20.48%), ...200717239495
miltefosine affects lipid metabolism in leishmania donovani promastigotes.miltefosine (hexadecylphosphocholine [hepc]) is the first orally active antileishmanial drug. transient hepc treatment of leishmania donovani promastigotes at 10 microm significantly reduced the phosphatidylcholine content and enhanced the phosphatidylethanolamine (pe) content in parasite membranes, suggesting a partial inactivation of pe-n-methyltransferase. phospholipase d activity did not seem to be affected by hepc. in addition, the enhancement of the lysophosphatidylcholine content could be ...200717242145
indel-based targeting of essential proteins in human pathogens that have close host orthologue(s): discovery of selective inhibitors for leishmania donovani elongation factor-1alpha.we propose a novel strategy for selective targeting of essential pathogen proteins that contain sizable indels (insertions/deletions) in their sequences compared with their host orthologues. this approach has been tested on elongation factor-1alpha (ef-1alpha) from the protozoan pathogen leishmania donovani. leishmania ef-1alpha is 82% identical to the corresponding human orthologue, but possesses a 12 aminoacid sequence deletion compared with human ef-1alpha. we used this indel-differentiated r ...200717243179
limonoid orthoacetates and antiprotozoal compounds from the roots of pseudocedrela kotschyi.the dicholoromethane extract of pseudocedrela kotschyi root demonstrated marked antileishmanial properties in preliminary screening of extracts from 21 species commonly used in malian traditional medicine. phytochemical investigation of the active extract yielded three novel phragmalin-type limonoid orthoacetates (1-3), named kotschyins a-c, and the known compounds 7-deacetylgedunin (4) and 7-deacetyl-7-oxogedunin (5). the structures of 1-3 were elucidated by analytical methods including 1d- and ...200717253841
molecular dissection and expression of the ldk39 kinesin in the human pathogen, leishmania donovani.in this study we show for the first time the intracellular distribution of a k39 kinesin homologue in leishmania donovani, a medically important parasite of humans. further, we demonstrated that this motor protein is expressed in both the insect and mammalian developmental forms (i.e. promastigote and amastigotes) of this organism. moreover, in both of these parasite developmental stages, immunofluorescence indicated that the ldk39 kinesin accumulated at anterior and posterior cell poles and tha ...200717257310
the role of mannose receptor during experimental leishmaniasis.the primary host cells for leishmania replication are macrophages (mp). several molecules on the surface of professional phagocytic cells have been implicated in the initial process of parasite internalization and initiation of signaling pathways. these pattern recognition receptors distinguish molecular patterns on pathogen surfaces. mannose receptor (mr), specifically, recognizes mannose residues on the surface of leishmania parasites. we studied the role of mr in the pathogenesis of experimen ...200717261547
degradation of pteridine reductase 1 (ptr1) enzyme during growth phase in the protozoan parasite leishmania donovani.pteridine reductase 1 (ptr1) is an essential enzyme of pterin and folate metabolism in the protozoan parasite leishmania. the present work is focused on the degradation of ptr1 during growth phase in leishmania donovani. western blot analysis with ptr1-gfp transfected promastigotes revealed that ptr1 protein was degraded in the stationary phase of growth at the time when the parasites were undergoing metacyclogenesis. fluorescence microscopy revealed cytoplasmic localization of gfp tagged protei ...200717275814
molecular and functional analyses of a novel class i secretory nuclease from the human pathogen, leishmania donovani.the primitive protozoan pathogen of humans, leishmania donovani, resides and multiplies in highly restricted micro-environments within their hosts (i.e. as promastigotes in the gut lumen of their sandfly vectors and as amastigotes in the phagolysosomal compartments of infected mammalian macrophages). like other trypanosomatid parasites, they are purine auxotrophs (i.e. lack the ability to synthesize purines de novo) and therefore are totally dependent upon salvaging these essential nutrients fro ...200717276983
structure of cyclophilin from leishmania donovani at 1.97 a resolution.the crystal structure of cyclophilin from leishmania donovani (ldcyp) has been determined and refined at 1.97 a resolution to a crystallographic r factor of 0.178 (r(free) = 0.197). the structure was solved by molecular replacement using cyclophilin from trypanosoma cruzi as the search model. ldcyp exhibits complete structural conservation of the cyclosporin-binding site with respect to the homologous human protein, as anticipated from ldcyp-cyclosporin binding studies. comparisons with other cy ...200717277440
ornithine decarboxylase and s-adenosylmethionine decarboxylase in trypanosomatids.the production of polyamines has been shown to be an effective target for a drug against the west african form of sleeping sickness caused by trypanosoma brucei gambiense. t. brucei belongs to the group of protozoan parasites classed as trypanosomatids. parasitic species of this group are the causative agents of various tropical diseases besides african sleeping sickness, e.g. chagas' disease (trypanosoma cruzi), cutaneous (lesihmania spp.) and visceral (leishmania donovani) leishmaniasis. the m ...200717371268
amphotericin b-gum arabic conjugates: synthesis, toxicity, bioavailability, and activities against leishmania and fungi.gum arabic, a branched polysaccharide consisting of more than 90% arabinogalactan having a molecular weight around 250,000 da is the oldest and best known of all natural gums. the objective of the present investigation was to examine whether amphotericin b (amb), the polyene antibiotic when conjugated to periodate oxidized gum arabic still retained its anti-fungal and anti-leishmanial activity and to evaluate its toxicity and bioavailability.200717372682
sodium stibogluconate-sensitive visceral leishmaniasis in the non-endemic hilly region of uttarakhand, india.although visceral leishmaniasis (vl) is endemic in various parts of india, mainly bihar, west bengal and orissa, and neighbouring countries such as nepal and bangladesh, it is rarely reported from the hilly areas of india. we report on nine male vl cases from the non-endemic garhwal region of uttarakhand who were treated successfully with sodium stibogluconate. we conclude that sodium stibogluconate-sensitive vl is emerging in this region and that urgent and effective vector control measures may ...200717382981
the hunt for an elusive source of pyrexia in a foreign worker.we report a 23-year-old bangladeshi man who presented with fever and hepatosplenomegaly. the initial laboratory findings were bicytopenia with elevated serum globulins. the diagnosis of visceral leishmaniasis (kala azar) was suspected. the parasite leishmania donovani was found on bone marrow aspiration. he was treated with liposomal amphotericin b and had a good response to treatment. the case highlights the need to be aware of this disease occurring in a foreign national from an endemic region ...200717384865
splenic accumulation of il-10 mrna in t cells distinct from cd4+cd25+ (foxp3) regulatory t cells in human visceral leishmaniasis.visceral leishmaniasis (vl) is a life-threatening disease characterized by uncontrolled parasitization of the spleen, liver, and bone marrow. interleukin (il)-10 has been implicated in the suppression of host immunity in human vl based on the elevated levels of il-10 observed in plasma and lesional tissue, and its role in preventing clearance of leishmania donovani in murine models of vl. the aim of this study was to identify the cellular source of il-10 in human vl and determine if cd4(+)cd25(+ ...200717389235
nk cell activation in visceral leishmaniasis requires tlr9, myeloid dcs, and il-12, but is independent of plasmacytoid dcs.natural killer (nk) cells are sentinel components of the innate response to pathogens, but the cell types, pathogen recognition receptors, and cytokines required for their activation in vivo are poorly defined. here, we investigated the role of plasmacytoid dendritic cells (pdcs), myeloid dcs (mdcs), toll-like receptors (tlrs), and of nk cell stimulatory cytokines for the induction of an nk cell response to the protozoan parasite leishmania infantum. in vitro, pdcs did not endocytose leishmania ...200717389237
hla class i-restricted t cell epitopes of the kinetoplastid membrane protein-11 presented by leishmania donovani-infected human macrophages.visceral leishmaniasis is a protozoal disease caused by the intracellular parasites leishmania donovani and l. chagasi/infantum, and it is usually deadly if not treated. to date, no vaccine exists for prophylaxis or immunotherapy, nor has it been established which effector mechanisms of the immune system are most instrumental against the parasites. recent reports have suggested that cd8(+) t cells, in addition to cd4(+) t cells, might play major roles in the defense against infection and in the ...200717397010
molecular architecture of leishmania ef-1alpha reveals a novel site that may modulate protein translation: a possible target for drug development.elongation factor-1alpha plays an essential role in eukaryotic protein biosynthesis. recently, we have shown by protein structure modeling the presence of a hairpin-loop of 12 amino acids in mammalian ef-1alpha that is absent in the leishmania homologue [d. nandan, a. cherkasov, r. sabouti, t. yi, n.e. reiner, molecular cloning, biochemical and structural analysis of elongation factor-1 alpha from leishmania donovani: comparison with the mammalian homologue, biochem. biophys. res. commun. 302 (2 ...200717397800
synthesis of isoquinuclidine analogs of chloroquine: antimalarial and antileishmanial activity.the isoquinuclidine (2-azabicyclo[2.2.2]octane) ring system may be viewed as a semi-rigid boat form of the piperidine ring and, when properly substituted, a scaffold for rigid analogs of biologically active ethanolamines and propanolamines. it is present in natural products (such as ibogaine and dioscorine) that display interesting pharmacological properties. in this study, we have expanded our continuing efforts to incorporate this ring system in numerous pharmacophores, by designing and synthe ...200717400457
circulating immune complexes (ic) and ic-induced levels of gm-csf are increased in sudanese patients with acute visceral leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis.infection with leishmania donovani is associated with il-10 as well as with gm-csf. immune complexes (ic) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. in this investigation, we have explored ic-induced cytokine production during leishmania infection. sera from 43 patients with visceral leishmaniasis (vl), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy sudanese controls wer ...200717404324
[laryngeal leishmaniasis].leishmaniasis consists in a zoonotic infection, that means affect animals. due to the puncture of the female sand fly type phlebotomus (ancient world) or lutzomya (new world) the human being can be also affected. the clinical manifestations are very varied, depending to factors related with host, vector and the proper parasit. in this present work, we expose the three unic cases of leishmaniasis affecting the larynx, diagnosticated in the sanitary area of toledo. due to the specific characterist ...200717405455
a structural insight into the inhibition of human and leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane.the critical role of polyamines in key processes such as cell growth, differentiation and macromolecular synthesis makes the enzymes involved in their synthesis potential targets in the treatment of certain types of cancer and parasitic diseases. here we present a study on the inhibition of human and leishmania donovani odc (ornithine decarboxylase), the first committed enzyme in the polyamine biosynthesis pathway, by apa (1-amino-oxy-3-aminopropane). the present study shows apa to be a potent i ...200717407445
nuclear localization of an actin-related protein (orf lmjf21.0230) in leishmania+. 200717408765
how to diagnose and manage common parasitic pneumonias.parasitic pneumonia is being increasingly reported from many parts of the world due to globalization and travel across the continents. this review outlines the recent developments in the diagnosis and management of parasitic pneumonias.200717414130
dna vaccination against the parasite enzyme gamma-glutamylcysteine synthetase confers protection against leishmania donovani infection.in this study the potential of using leishmania donovani gamma-glutamylcysteine synthetase (glutamate-cysteine ligase, gamma-gcs) as a rational target for vaccine development was determined. mice, immunised with plasmid containing the full gene sequence for gamma-gcs (pvaxgammagcs) or plasmid alone (pvax control), were challenged with a high dose of l. donovani amastigotes to give a stringent test of the ability of the vaccine to protect against infection. vaccination with pvaxgammagcs resulted ...200717418459
characterization of natural antimony resistance in leishmania donovani isolates.clinical resistance to pentavalent antimonial compounds has long been recognized as a major problem in the treatment of visceral leishmaniasis in india. however, mechanisms of natural resistance are unclear. in this study, we observed that leishmania donovani clinical isolates not responsive to sodium stibogluconate showed resistance to antimony treatment in both in vitro and in vivo laboratory conditions. the resistant isolates have increased levels of intracellular thiols. this increase in thi ...200717426170
synthesis, dna binding, and leishmania topoisomerase inhibition activities of a novel series of anthra[1,2-d]imidazole-6,11-dione derivatives.nine novel anthra[1,2-d]imidazole-6,11-diones, differing in their side chain, were synthesized. uv-vis spectroscopy and viscometric titrations of these molecules with duplex dna were used to assess their binding with dna. five of the nine compounds showed high inhibition activity against topoisomerase i of leishmania donovani, with the one bearing the tetrazole side chain exhibiting an ic50 approximately 1 microm. the inhibition activities were not related with their dna binding affinity and dep ...200717444624
aloe vera leaf exudate induces a caspase-independent cell death in leishmania donovani promastigotes.leishmaniasis constitutes a complex of diseases with clinical and epidemiological diversity and includes visceral leishmaniasis, a disease that is fatal when left untreated. in earlier studies, the authors reported that aloe vera leaf exudate (avl) is a potent antileishmanial agent effective in promastigotes of leishmania braziliensis, leishmania mexicana, leishmania tropica, leishmania major and leishmania infantum and also in axenic amastigotes of leishmania donovani. in the present study, it ...200717446285
antileishmanial 2-substituted quinolines: in vitro behaviour towards biological components.quinolines substituted on their carbon 2 have in vivo antileishmanial activity but some of them could not be detected in plasma when assayed for pharmacokinetic studies, suggesting a sequestration of the drugs by components of the blood compartment. the present study, performed on three quinolines (1, 2 and 3), showed strong affinity for two of them (2 and 3) with red blood cells (rbcs), whereas quinoline 1 did not react with them. this process was saturable, temperature dependant and positively ...200717459651
lack of cxcr3 delays the development of hepatic inflammation but does not impair resistance to leishmania donovani.cxc chemokine receptor 3 (cxcr3) ligands cxcl9 and cxcl10 are produced at high levels in mice and humans infected with leishmania donovani, but their contribution to host resistance against l. donovani is not clear. here, using cxcr3(-/-) mice, we demonstrate that, although cxcr3 regulates early immune cell trafficking and hepatic inflammation during l. donovani infection, it is not essential for immunity against l. donovani, unlike l. major. cxcr3(-/-) c57bl/6 mice show a delayed onset of hepat ...200717471442
assessment of the monoterpene, glycidic and triterpene-moieties' contributions to the adjuvant function of the cp05 saponin of calliandra pulcherrima benth during vaccination against experimental visceral leishmaniasis.the cp05 saponin from calliandra pulcherrima benth, shows remarkable similarities to the qs21 saponin of quillaja saponaria molina. both shared a monoterpene hydrophobic moiety, a glycidic chain attached to the triterpene c28, and three sugars attached to c3. different from qs21, the cp05 does not show the aldehyde group in triterpene c4 involved in th1 response. balb/c mice were immunized either intact saponin (cp05), the monoterpene-deprived (bs), the c28 carbohydrate-deprived (hs) or the sapo ...200717014936
genetic heterogeneity among visceral and post-kala-azar dermal leishmaniasis strains from eastern india.in india and sudan, some patients of visceral leishmaniasis develop post-kala-azar dermal leishmaniasis (pkdl) while majority will not. similarly, the clinical manifestations and treatment outcome are reported to vary from district to district and state to state in india. present study is focused on to find out the genetic variations between vl & pkdl causing strains. nuclear dna from 24 strains of leishmania donovani, isolated from patients of visceral leishmaniasis (18) and pkdl (6) was extrac ...200717027344
leishmania donovani: dyskinetoplastid cells survive and proliferate in the presence of pyruvate and uridine but do not undergo apoptosis after treatment with camptothecin.we have shown that treatment with luteolin in leishmanial cells causes loss of mt-dna and induces apoptosis through mitochondria dependent pathway [sen, n., das, b.b., ganguly, a., banerjee, b., sen, t., majumder, h.k., 2006. leishmania donovani: intracellular atp level regulates apoptosis-like death in luteolin induced dyskinetoplastid cells. experimental parasitology, in press]. here, we report that mitochondrial dna depleted leishmanial cells require exogenous sources of pyruvate and uridine ...200717027973
the leishmania donovani complex: genotypes of five metabolic enzymes (icd, me, mpi, g6pdh, and fh), new targets for multilocus sequence typing.flagellates of the leishmania donovani complex are causative agents of human cutaneous and visceral leishmaniasis. the complex is comprised of l. donovani, leishmania infantum and leishmania archibaldi, although the latter is not now considered to be a valid species. morphological distinction of leishmania species is impractical, so biochemical, immunological and dna-based criteria were introduced. multilocus enzyme electrophoresis (mlee) is the present gold standard. we have sequenced the genes ...200717027989
the ugi reaction in the generation of new nucleosides as potential antiviral and antileishmanial agents.5-formyl-2'-deoxyuridine-3',5'-diacetate was converted to a small library of 5-substituted pyrimidine nucleoside n-acylamino acid amides by means of a ugi multicomponent reaction. the reaction allowed introduction of various substituents at the acyl moiety, at the amino acid alpha-amide group, and at the amino acid carboxyl function. evaluation of these novel 5-substituted nucleosides against vaccinia virus and cowpox virus provided one compound with discernable activity against cowpox virus but ...200716996561
epidemiological dynamics of antimonial resistance in leishmania donovani: genotyping reveals a polyclonal population structure among naturally-resistant clinical isolates from nepal.pentavalent antimonials (sbv) are the first line drug against leishmaniasis worldwide, but drug resistance is increasingly reported, particularly in the indian sub-continent, where it represents a major threat for the control of anthroponotic visceral leishmaniasis (vl). in order to understand the epidemiological dynamics of antimonial resistance in anthroponotic vl, we analysed here the population structure of 24 leishmania donovani stocks isolated from anthroponotic vl-patients from eastern ne ...200717010679
translation of open reading frame in kinetoplast dna minicircles of clinical isolates of l. donovani.till today, it remains an enigma whether the open reading frames said to be transcribed in minicircle sequences are indeed translated into protein products or not. we establish a protein-coding gene in minicircle variable region of kinetoplast dna from clinical isolates of leishmania donovani. the protein was expressed as an n-tagged green fluorescent protein (gfp) fusion protein in leishmanial expression system. fluorescence microscopy of the transfectants carrying recombinant gfp construct sho ...200717047999
a proteomics screen implicates hsp83 and a small kinetoplastid calpain-related protein in drug resistance in leishmania donovani clinical field isolates by modulating drug-induced programmed cell death.the therapeutic mainstay against the protozoan parasite leishmania is still based on the antiquated pentavalent antimonials (sb(v)), but resistance is increasing in several parts of the world. resistance is now partly understood in laboratory isolates, but our understanding of resistance in field isolates is lagging behind. we describe here a comparative analysis of a genetically related pair of sb(v)-sensitive and -resistant leishmania donovani strains isolated from kala-azar patients. the resi ...200717050524
antiprotozoal and antimicrobial activities of o-alkylated and formylated acylphloroglucinols.in the present article, we examined the antileishmanial, antimalarial, antibacterial, and antifungal activities of several newly synthesized o-alkylated phloroglucinol compounds (11-19) which are analogues of the naturally occurring antimalarial compound 1. analogues 12 and 16 exhibited antileishmanial activity against, leishmania donovani promastigotes with ic(50)s of 5.3 and 4.2microg/ml, respectively. naturally occurring monomeric formylated acylphloroglucinol compounds, grandinol (2), jensen ...200717070063
synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (methb) formation activities of new 8-quinolinamines.we report the synthesis, in vitro antiprotozoal (against plasmodium and leishmania), antimicrobial, cytotoxicity (vero and methb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. n1-{4-[2-(tert-butyl)-6-methoxy-8-quinolylamino]pentyl}-(2s/2r)-2-aminosubstitutedamides (21-33) and n1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2s/2r)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methox ...200717084633
antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion.the polyamines putrescine, spermidine, and spermine are organic cations that are required for cell growth and differentiation. ornithine decarboxylase (odc), the first and rate-limiting enzyme in the polyamine biosynthetic pathway, catalyzes the conversion of ornithine to putrescine. as the polyamine biosynthetic pathway is essential for the growth and survival of leishmania donovani, the causative agent of visceral leishmaniasis, inhibition of the pathway is an important leishmaniacidal strateg ...200717101681
identification of the benzodiazepines as a new class of antileishmanial agent.the continual increase in drug resistance; the lack of new chemotherapeutic agents; the toxicity of existing agents and the increasing morbidity with hiv co-infection mean the search for new antileishmanial agents has never been more urgent. we have identified the benzodiazepines as a structural class for antileishmanial hit optimisation, and demonstrated that their in vitro activity is comparable with the clinically used drug, sodium stibogluconate, and that the compounds are not toxic to macro ...200717113290
leishmania donovani polyamine biosynthetic enzyme overproducers as tools to investigate the mode of action of cytotoxic polyamine analogs.a number of anticancer and antiparasitic drugs are postulated to target the polyamine biosynthetic pathway and polyamine function, but the exact mode of action of these compounds is still being elucidated. to establish whether polyamine analogs specifically target enzymes of the polyamine pathway, a model was developed using strains of the protozoan parasite leishmania donovani that overproduce each of the polyamine biosynthetic enzymes. promastigotes overexpressing episomal constructs encoding ...200717116678
specific cpb copies within the leishmania donovani complex: evolutionary interpretations and potential clinical implications in humans.leishmania infantum and leishmania donovani both pertain to the l. (l.) donovani complex and are responsible for visceral leishmaniasis. to explore the l. donovani complex, we focused our study on cysteine protease b (cpb) and especially on 2 cpb copies: cpbe and cpbf. we selected cpb genes because of their phylogenetic interest and host-parasite interaction involvement. sequencing these 2 copies revealed (i) that cpbe is specific to l. infantum and cpbf is specific to l. donovani and (ii) that ...200717129395
synthesis and evaluation of isosteres of n-methyl indolo[3,2-b]-quinoline (cryptolepine) as new antiinfective agents.isosteres of cryptolepine (1) were synthesized and evaluated for their antiinfective activities. overall, the sulfur isostere, 5-methyl benzothieno[3,2-b]quinolinium salt (5b), was equipotent to 1 and has shown no cytotoxicity at 23.8 microg/ml. compound 5b was also found to have a broad spectrum of activity. both the carbon and oxygen isosteres were less potent than cryptolepine. a limited library of 2-substituted analogs of 5b has been synthesized and evaluated in antifungal screens but did no ...200717134906
in vitro antiprotozoal activities and cytotoxicity of some selected cameroonian medicinal plants.eight extracts from seven selected cameroonian medicinal plants, traditionally used to treat malaria and other protozoal diseases, were tested in vitro for their antiprotozoal activities against plasmodium falciparum k1 chloroquine-resistant strain, leishmania donovani, trypanosoma cruzi and trypanosoma brucei rhodesiense, protozoa responsible for malaria, visceral leishmaniasis, chagas disease and african trypanosomiasis, respectively. the most active extract against plasmodium falciparum k1 st ...200717141994
molecular cloning and biochemical characterization of leishmania donovani serine hydroxymethyltransferase.serine hydroxymethyltransferase (shmt) catalyzes the inter conversion of serine and tetrahydrofolate (h(4)-folate) to form glycine and 5,10-methylene h(4)-folate and generates one-carbon fragments for the synthesis of nucleotides, methionine, thymidylate, choline, etc. in spite of being an indispensable enzyme of the thymidylate cycle, shmt in leishmania donovani remains uncharacterized. the study of l. donovani shmt (ldshmt) becomes important as this gene is preferentially expressed in the amas ...200717142057
balancing immunity and pathology in visceral leishmaniasis.experimental visceral leishmaniasis (vl) caused by infection with leishmania donovani results in the development of organ-specific immunity in the two main target tissues of infection, the spleen and the liver. the liver is the site of an acute resolving infection associated with the development of inflammatory granulomas around infected kupffer cells, and resistance to reinfection. paradoxically, the spleen is an initial site for the generation of cell-mediated immune responses, but ultimately ...200717146466
in vitro antileishmanial activity of aloe vera leaf exudate: a potential herbal therapy in leishmaniasis.aloe vera has wide spread use in health products, and despite several reports on the whole plant and inner gel, little work has been performed on the leaf exudate. our aim was to evaluate the in vitro efficacy of aloe vera leaf exudate (avl) in leishmaniasis. irrespective of the disease manifestation, promastigotes from strains responsible for cutaneous, mucocutaneous, and visceral leishmaniasis were susceptible to avl and their ic(50) ranged from 100 to 180 microg/ml. in axenic amastigotes cult ...200717146713
bioinformatic identification of tandem repeat antigens of the leishmania donovani complex.with large amounts of parasite gene sequence available, additional bioinformatic tools to screen these sequences for identifying genes encoding antigens are needed. proteins containing tandem repeat (tr) domains are often b-cell antigens, and antibody responses toward tr domains of the proteins are dominant in human infected with certain parasites. we hypothesized that antigens of serological significance could be identified with a search for tr domains. here we show the result of bioinformatic ...200717088350
development and validation of rp-hplc-uv method for simultaneous determination of buparvaquone, atenolol, propranolol, quinidine and verapamil: a tool for the standardization of rat in situ intestinal permeability studies.a simple, sensitive and specific reversed phase high performance liquid chromatographic (rp-hplc) method with uv detection at 251 nm was developed for simultaneous quantitation of buparvaquone (bpq), atenolol, propranolol, quinidine and verapamil. the method was applicable in rat in situ intestinal permeability study to assess intestinal permeability of bpq, a promising lead compound for leishmania donovani infections. the method was validated on a c-4 column with mobile phase comprising ammoniu ...200717157469
3d-quantitative structure-activity relationships of synthetic antileishmanial ring-substituted ether phospholipids.the application of 2d-nmr spectroscopy and molecular modeling in determining the active conformation of flexible molecules in 3d-qsar was demonstrated in the present study. in particular, a series of 33 flexible synthetic phospholipids, either 2-(4-alkylidene-cyclohexyloxy)ethyl- or omega-cycloalkylidene-substituted ether phospholipids were systematically evaluated for their in vitro antileishmanial activity against the promastigote forms of leishmania infantum and leishmania donovani by comfa a ...200717158053
possibility of membrane modification as a mechanism of antimony resistance in leishmania donovani.resistance to antimonials has become a clinical threat in the treatment of visceral leishmaniasis (vl). unravelling the resistance mechanism needs attention to circumvent the problem of drug resistance. in one of the resistant isolates, we earlier identified a gene (pg1) implicated in antimony resistance whose localization in the present study was confirmed on the pellicular plasma membrane of the parasite thereby indicating towards membrane modification as a mechanism of resistance in this resi ...200717169604
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