Effect of the aggregated protein dye YAT2150 on Leishmania parasite viability.

The problems associated with the drugs currently used to treat leishmaniasis, including resistance, toxicity, and the high cost of some formulations, call for the urgent identification of new therapeutic agents with novel modes of action. The aggregated protein dye YAT2150 has been found to be a potent antileishmanial compound, with a half-maximal inhibitory concentration (IC50) of approximately 0.5 µM against promastigote and amastigote stages of Leishmania infantum. The encapsulation in liposomes of YAT2150 significantly improved its in vitro IC50 to 0.37 and 0.19 µM in promastigotes and amastigotes, respectively, and increased the half-maximal cytotoxic concentration in human umbilical vein endothelial cells to >50 µM. YAT2150 became strongly fluorescent when binding intracellular protein deposits in Leishmania cells. This fluorescence pattern aligns with the proposed mode of action of this drug in the malaria parasite Plasmodium falciparum, the inhibition of protein aggregation. In Leishmania major, YAT2150 rapidly reduced ATP levels, suggesting an alternative antileishmanial mechanism. To the best of our knowledge, this first-in-class compound is the only one described so far having significant activity against both Plasmodium and Leishmania, thus being a potential drug for the treatment of co-infections of both parasites.

Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis.

Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy.

Hybrid Cyclobutane/Proline-Containing Peptidomimetics: The Conformational Constraint Influences Their Cell-Penetration Ability.

A new family of hybrid ß,γ-peptidomimetics consisting of a repetitive unit formed by a chiral cyclobutane-containing trans-ß-amino acid plus a Nα-functionalized trans-γ-amino-l-proline joined in alternation were synthesized and evaluated as cell penetrating peptides (CPP). They lack toxicity on the human tumoral cell line HeLa, with an almost negligible cell uptake. The dodecapeptide showed a substantial microbicidal activity on Leishmania parasites at 50 µM but with a modest intracellular accumulation. Their previously published γ,γ-homologues, with a cyclobutane γ-amino acid, showed a well-defined secondary structure with an average inter-guanidinium distance of 8-10 Å, a higher leishmanicidal activity as well as a significant intracellular accumulation. The presence of a very rigid cyclobutane ß-amino acid in the peptide backbone precludes the acquisition of a defined conformation suitable for their cell uptake ability. Our results unveiled the preorganized charge-display as a relevant parameter, additional to the separation among the charged groups as previously described. The data herein reinforce the relevance of these descriptors in the design of CPPs with improved properties.

Diagnosis and Treatment of Parasellar Lesions.

The parasellar region, located around the sella turcica, is an anatomically complex area representing a crossroads for important adjacent structures. Several lesions, including tumoral, inflammatory vascular, and infectious diseases may affect this area. Although invasive pituitary tumors are the most common neoplasms encountered within the parasellar region, other tumoral (and cystic) lesions can also be detected. Craniopharyngiomas, meningiomas, as well as Rathke's cleft cysts, chordomas, and ectopic pituitary tumors can primarily originate from the parasellar region. Except for hormone-producing ectopic pituitary tumors, signs and symptoms of these lesions are usually nonspecific, due to a mass effect on the surrounding anatomical structures (i.e., headache, visual defects), while a clinically relevant impairment of endocrine function (mainly anterior hypopituitarism and/or diabetes insipidus) can be present if the pituitary gland is displaced or compressed. Differential diagnosis of parasellar lesions mainly relies on magnetic resonance imaging, which should be interpreted by neuroradiologists skilled in base skull imaging. Neurosurgery is the main treatment, alone or in combination with radiotherapy. Of note, recent studies have identified gene mutations or signaling pathway modulators that represent potential candidates for the development of targeted therapies, particularly for craniopharyngiomas and meningiomas. In summary, parasellar lesions still represent a diagnostic and therapeutic challenge. A deeper knowledge of this complex anatomical site, the improvement of imaging tools, as well as novel insights into the pathophysiology of presenting lesions are strongly needed to improve the management of parasellar lesions.

The effect of iron on Trichomonas vaginalis TvCP2: a cysteine proteinase found in vaginal secretions of trichomoniasis patients.

Trichomonas vaginalis (Tv) induces host cell damage through cysteine proteinases (CPs) modulated by iron. An immunoproteomic analysis showed that trichomoniasis patient sera recognize various CPs, also some of them are present in vaginal washes (VWs). Thus, the goal of this work was to determine whether TvCP2 is expressed during infection and to assess the effect of iron on TvCP2 expression, localization and contribution to in vitro cellular damage. Western-blotting (WB) assays using TvCP2r and vaginitis patient serum samples showed that 6/9 Tv (+) but none of the Tv (-) patient sera recognized TvCP2r. WB using an anti-TvCP2r antibody and VWs from the same patients showed that in all of the Tv (+) but none of the Tv (-) VWs, the anti-TvCP2r antibody detected a 27 kDa protein band that corresponded to the mature TvCP2, which was confirmed by mass spectrometry analysis. Iron decreased the amount of TvCP2 mRNA and the protein localized on the parasite surface and cytoplasmic vesicles concomitant with the cytotoxic effect of TvCP2 on HeLa cells. Parasites pretreated with the anti-TvCP2r antibody also showed reduced levels of cytotoxicity and apoptosis induction in HeLa cell monolayers. In conclusion, these results show that TvCP2 is expressed during trichomonal infection and plays an important role in the in vitro HeLa cell cytotoxic damage under iron-restricted conditions.

Towards discovery of new leishmanicidal scaffolds able to inhibit Leishmania GSK-3.

Previous reports have validated the glycogen synthase kinase-3 (GSK-3) as a druggable target against the human protozoan parasite Leishmania. This prompted us to search for new leishmanicidal scaffolds as inhibitors of this enzyme from our in-house library of human GSK-3ß inhibitors, as well as from the Leishbox collection of leishmanicidal compounds developed by GlaxoSmithKline. As a result, new leishmanicidal inhibitors acting on Leishmania GSK-3 at micromolar concentrations were found. These inhibitors belong to six different chemical classes (thiadiazolidindione, halomethylketone, maleimide, benzoimidazole, N-phenylpyrimidine-2-amine and oxadiazole). In addition, the binding mode of the most active compounds into Leishmania GSK-3 was approached using computational tools. On the whole, we have uncovered new chemical scaffolds with an appealing prospective in the development and use of Leishmania GSK-3 inhibitors against this infectious protozoan.

Effect of substituents in the A and B rings of chalcones on antiparasite activity.

Chalcones are a group of natural products with many recognized biological activities, including antiparasitic activity. Although a lot of chalcones have been synthetized and assayed against parasites, the number of structural features known to be involved in this biological property is small. Thus, in the present study, 21 chalcones were synthesized to determine the effect of substituents in the A and B rings on the activity against Leishmania braziliensis, Trypanosoma cruzi, and Plasmodium falciparum. The compounds were active against L. braziliensis in a structure-dependent manner. Only one compound was very active against T. cruzi, but none of them had a significant antiplasmodial activity. The electron-donating substituents in ring B and the hydrogen bonds at C-2' with carbonyl affect the antiparasitic activity.

Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems.

Two series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1S,2R)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a Nα-functionalized cis- or trans-γ-amino-l-proline derivative, respectively, have been synthesized and evaluated as cell penetrating peptides (CPP) and as selective vectors for anti-Leishmania drug delivery systems (DDS). They lacked cytotoxicity on the tumoral human cell line HeLa with a moderate cell-uptake on these cells. In contrast, both γ-CC and γ-CT tetradecamers were microbicidal on the protozoan parasite Leishmania beyond 25 µM, with significant intracellular accumulation. They were conjugated to fluorescent doxorubicin (Dox) as a standard drug showing toxicity beyond 1 µM, while free Dox was not toxic. Intracellular accumulation was 2.5 higher than with Dox-TAT conjugate (TAT = transactivator of transcription, taken as a standard CPP). The conformational structure of the conjugates was approached both by circular dichroism spectroscopy and molecular dynamics simulations. Altogether, computational calculations predict that the drug-γ-peptide conjugates adopt conformations that bury the Dox moiety into a cavity of the folded peptide, while the positively charged guanidinium groups face the solvent. The favorable charge/hydrophobicity balance in these CPP improves the solubility of Dox in aqueous media, as well as translocation across cell membranes, making them promising candidates for DDS.

Cyanobacteria and Eukaryotic Microalgae as Emerging Sources of Antibacterial Peptides.

Cyanobacteria and microalgae are oxygen-producing photosynthetic unicellular organisms encompassing a great diversity of species, which are able to grow under all types of extreme environments and exposed to a wide variety of predators and microbial pathogens. The antibacterial compounds described for these organisms include alkaloids, fatty acids, indoles, macrolides, peptides, phenols, pigments and terpenes, among others. This review presents an overview of antibacterial peptides isolated from cyanobacteria and microalgae, as well as their synergism and mechanisms of action described so far. Antibacterial cyanopeptides belong to different orders, but mainly from Oscillatoriales and Nostocales. Cyanopeptides have different structures but are mainly cyclic peptides. This vast peptide repertoire includes ribosomal and abundant non-ribosomal peptides, evaluated by standard conventional methodologies against pathogenic Gram-negative and Gram-positive bacteria. The antibacterial activity described for microalgal peptides is considerably scarcer, and limited to protein hydrolysates from two Chlorella species, and few peptides from Tetraselmis suecica. Despite the promising applications of antibacterial peptides and the importance of searching for new natural sources of antibiotics, limitations still persist for their pharmaceutical applications.

Cyanobacterial peptides as a tour de force in the chemical space of antiparasitic agents.

Parasites are scarcely addressed target for antimicrobial peptides despite their big impact in health and global economy. The notion of antimicrobial peptides is frequently associated to the innate immune defense of vertebrates and invertebrate vectors, as the ultimate recipients of the parasite infection. These antiparasite peptides are produced by ribosomal synthesis, with few post-translational modifications, and their diversity come mostly from their amino acid sequence. For many of them permeabilization of the cell membrane of the targeted pathogen is crucial for their microbicidal mechanism. In contrast, cyanobacterial peptides are produced either by ribosomal or non-ribosomal biosynthesis. Quite often, they undergo heavy modifications, such as the inclusion of non-proteinogenic amino acids, lipid acylation, cyclation, Nα-methylation, or heterocyclic rings. Furthermore, the few targets identified for cyanobacterial peptides in parasites are intracellular. Some cyanobacterial antiparasite peptides are active at picomolar concentrations, whereas those from higher eukaryotes usually work in the micromolar range. In all, cyanobacterial peptides are an appealing target to develop new antiparasite therapies and a challenge in the invention of new synthetic methods for peptides. This review aims to provide an updated appraisal of antiparasite cyanobacterial peptides and to establish a side-by -side comparison with those antiparasite peptides from higher eukaryotes.

Aggressive and Malignant Prolactinomas.

Prolactin-secreting tumors (prolactinomas) represent the most common pituitary tumor type, accounting for 47-66% of functional pituitary tumors. Prolactinomas are usually benign and controllable tumors as they express abundant levels of dopamine type 2 receptor (D2), and can be treated with dopaminergic drugs, effectively reducing prolactin levels and tumor volume. However, a proportion of prolactinomas exhibit aggressive features (including invasiveness, relevant growth despite adequate dopamine agonist treatment, and recurrence potential) and few may exhibit metastasizing potential (carcinomas). In this context, the clinical, pathological, and molecular definitions of malignant and aggressive prolactinomas remain to be clearly defined, as primary prolactin-secreting carcinomas are similar to aggressive adenomas until the presence of metastases is detected. Indeed, standard molecular and histological analyses do not reflect differences between carcinomas and adenomas at a first glance and have limitations in prediction of the aggressive progression of prolactinomas, wherein the causes underlying the aggressive behavior remain unknown. Herein we present a comprehensive, multidisciplinary review of the most relevant epidemiological, clinical, pathological, genetic, biochemical, and molecular aspects of aggressive and malignant prolactinomas.

Glucose-restriction increases Trichomonas vaginalis cellular damage towards HeLa cells and proteolytic activity of cysteine proteinases (CPs), such as TvCP2.

Trichomonas vaginalis induces cellular damage to the host cells (cytotoxicity) through the proteolytic activity of multiple proteinases of the cysteine type (CPs). Some CPs are modulated by environmental factors such as iron, zinc, polyamines, etc. Thus, the goal of this study was to assess the effect of glucose on T. vaginalis cytotoxicity, proteolytic activity and the particular role of TvCP2 (TVAG_057000) during cellular damage. Cytotoxicity assays showed that glucose-restriction (GR) promotes the highest HeLa cell monolayers destruction (~95%) by trichomonads compared to those grown under high glucose (~44%) condition. Zymography and Western blot using different primary antibodies showed that GR increased the proteolytic activity, amount and secretion of certain CPs, including TvCP2. We further characterized the effect of glucose on TvCP2. TvCP2 increases in GR, localized in vesicles close to the plasma membrane and on the surface of T. vaginalis. Furthermore, pretreatment of GR-trichomonads with an anti-TvCP2r polyclonal antibody specifically reduced the levels of cytotoxicity and apoptosis induction to HeLa cells in a concentration-dependent manner. In conclusion, our data show that GR, as a nutritional stress condition, promotes trichomonal cytotoxicity to the host cells, increases trichomonad proteolytic activity and amount of CPs, such as TvCP2 involved in cellular damage.

Combination oral therapy against Leishmania amazonensis infection in BALB/c mice using nanoassemblies made from amphiphilic antimony(V) complex incorporating miltefosine.

Clinically available drugs for mucocutaneous and cutaneous leishmaniases (CL) include mainly pentavalent antimony (Sb(V)) complexes, liposomal amphotericin B, and miltefosine (HePC). However, they present at least one of the following limitations: long-term parenteral administration through repeated doses, severe side effects, drug resistance, and high cost. HePC is the only oral drug available, but the appearance of resistance has resulted in changes of its use from monotherapy to combination therapy. Amphiphilic Sb(V) complexes, such as SbL8 obtained from reaction of Sb(V) with N-octanoyl-N-methylglucamide, were recently found to be orally active against experimental CL. The property of SbL8 to self-assemble in aqueous solution, forming nanostructures, led us to investigate the incorporation of HePC into SbL8 nanoassemblies and the therapeutic efficacy of SbL8/HePC nanoformulation by oral route in a murine model of CL. HePC incorporation into the SbL8 nanosystem was evidenced by using a fluorescent analog of HePC. The antileishmanial activity of SbL8/HePC nanoassemblies was evaluated after daily oral administration for 30 days in Leishmania amazonensis-infected BALB/c mice, in comparison with monotherapies (SbL8 or HePC) and saline control. All the treatments resulted in significant reduction in the lesion size growth, when compared with control. Strikingly, only SbL8/HePC nanoassemblies promoted a significant decrease of the parasite burden in the lesion. This work establishes the therapeutic benefit of SbL8/HePC association by oral route in a CL model and constitutes an important step towards the development of new orally active drug combination.

Toward Digitalization of Maritime Transport?

Although maritime transport is the backbone of world commerce, its digitalization lags significantly behind when we consider some basic facts. This work verifies the state-of-the-art as it currently applies to eight digital domains: Autonomous vehicles and robotics; artificial intelligence; big data; virtual reality, augmented and mixed reality; internet of things; the cloud and edge computing; digital security; and 3D printing and additive engineering. It also provides insight into each of the three sectors into which this industry has been divided: Ship design and shipbuilding; shipping; and ports. The work, based on a systematic literature review, demonstrates that there are domains on which almost no formal study has been done thus far and concludes that there are major areas that require attention in terms of research. It also illustrates the increasing interest on the subject, arising from the necessity of raising the maritime transport industry to the same level of digitalization as other industries.

Ability of positive and negative contrast computed tomographic peritoneography to delineate canine liver lobe fissures.

OBJECTIVE: To determine the efficacy of contrast peritoneography in delineating liver lobe fissures by using computed tomography (CT). STUDY DESIGN: Prospective cross-sectional study. ANIMALS: Canine cadavers (n = 10). METHODS: An abdominal CT image of each cadaver was obtained under three conditions: without peritoneal contrast (precontrast), after insufflation of the peritoneal cavity with CO2 (negative contrast), and after intraperitoneal administration of iohexol (positive contrast). Images were reconstructed in three planes. Three reviewers independently scored each plane/contrast combination. Observers measured the length of each fissure in each plane. The measurable length of fissures was compared between techniques but was not compared with the actual length on cadavers. RESULTS: When assessment of all fissures was combined, measurements were obtained in 96 to 108 of 120 (80%-90%) positive contrast studies, 56 to 96 of 120 (47%-80%) negative contrast studies, and 12 to 32 of 120 (10%-27%) precontrast CT images. All observers measured fissures in all planes that were approximately two times longer on positive compared with negative contrast studies and two times longer on negative contrast studies compared with CT images without contrast. Measurable fissure lengths were greater on positive contrast CT images (P < .0001) than on other CT images. CONCLUSION: Positive contrast CT peritoneography improved the delineation of hepatic interlobar fissures in normal canine cadavers. CLINICAL SIGNIFICANCE: These results justify further studies to determine the ability to locate large hepatic masses in dogs with positive CT. Positive contrast CT peritoneography may assist treatment planning in dogs with large hepatic tumors.

Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate.

Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs against Leishmania share this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets in Leishmania were poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline on Leishmania infantum, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on the bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress in L. infantum promastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as a shortage of intracellular amino acids used as metabolic fuel by Leishmania Sertraline killed Leishmania through a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy.

The USP8 mutational status may predict long-term remission in patients with Cushing's disease.

OBJECTIVE: Almost half of the cases of Cushing's disease (CD) tumours carry recurrent activating somatic mutations in the ubiquitin-specific protease eight gene (USP8). The USP8 mutational status could predict remission in patients with CD, so our objective was to correlate the presence of somatic USP8 mutations with the rate of recurrence after transsphenoidal surgery (TSS) retrospectively. DESIGN: Biochemical, radiological and clinical data were retrospectively assessed in 48 patients. USP8 mutational status was determined from corticotroph tumour samples. Association between USP8 mutational status, remission and recurrence was investigated. PATIENTS: Patients with Cushing's disease from a single-centre cohort who underwent TSS between 1991 and 2012. MEASUREMENTS: Long-term remission and recurrence rate after TSS with at least 6 months follow-up. Biochemical, radiological and clinical data, including sex, age at diagnosis, tumour size and pre-operative hormonal levels. USP8 mutational status. RESULTS: Patients with USP8 mutant corticotroph tumours (18 of 48; 37%) were diagnosed significantly earlier (mean ± SD 46 ± 10 years vs 53 ± 11 years; P = 0.028) and presented with higher pre-operative 24-hour urinary-free cortisol levels (median IQR µg/24 hours 1174.0, 1184.5 vs 480.0, 405.3; P = 0.045). The incidence of recurrence in a 10-year follow-up was significantly higher in patients with USP8 mutant tumours after the initial remission (58% vs 18% P = 0.026). Recurrence appeared significantly earlier in these patients (months 70, 44-97 95% CI vs 102, 86-119 95% CI; P = 0.019). CONCLUSION: Recurrence appears to be more frequent and earlier after TSS in patients with USP8 mutant corticotroph tumours.

PATHOGENESIS OF CUSHING DISEASE: AN UPDATE ON THE GENETICS OF CORTICOTROPINOMAS.

OBJECTIVE: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically. METHODS: Literature review. RESULTS: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 ( USP8) gene in almost half of Cushing disease tumors. CONCLUSION: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease. ABBREVIATIONS: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8.

Enterocin AS-48 as Evidence for the Use of Bacteriocins as New Leishmanicidal Agents.

We report the feasibility of enterocin AS-48, a circular cationic peptide produced by Enterococcus faecalis, as a new leishmanicidal agent. AS-48 is lethal to Leishmania promastigotes as well as to axenic and intracellular amastigotes at low micromolar concentrations, with scarce cytotoxicity to macrophages. AS-48 induced a fast bioenergetic collapse of L. donovani promastigotes but only a partial permeation of their plasma membrane with limited entrance of vital dyes, even at concentrations beyond its full lethality. Fluoresceinated AS-48 was visualized inside parasites by confocal microscopy and seen to cause mitochondrial depolarization and reactive oxygen species production. Altogether, AS-48 appeared to have a mixed leishmanicidal mechanism that includes both plasma membrane permeabilization and additional intracellular targets, with mitochondrial dysfunctionality being of special relevance. This complex leishmanicidal mechanism of AS-48 persisted even for the killing of intracellular amastigotes, as evidenced by transmission electron microscopy. We demonstrated the potentiality of AS-48 as a new and safe leishmanicidal agent, expanding the growing repertoire of eukaryotic targets for bacteriocins, and our results provide a proof of mechanism for the search of new leishmanicidal bacteriocins, whose diversity constitutes an almost endless source for new structures at moderate production cost and whose safe use on food preservation is well established.

Leishmania infantum modulates host macrophage mitochondrial metabolism by hijacking the SIRT1-AMPK axis.

Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis.