@article{Schorn2021,

title = {A community resource for paired genomic and metabolomic data mining},

author = {Michelle A Schorn and Stefan Verhoeven and Lars Ridder and Florian Huber and Deepa D Acharya and Alexander A Aksenov and Gajender Aleti and Jamshid Amiri Moghaddam and Allegra T Aron and Saefuddin Aziz and Anelize Bauermeister and Katherine D Bauman and Martin Baunach and Christine Beemelmanns and Michael J Beman and Mar\'{i}a Victoria Berlanga-Clavero and Alex A Blacutt and Helge B Bode and Anne Boullie and Asker Brejnrod and Tim S Bugni and Alexandra Calteau and Liu Cao and V\'{i}ctor J Carri\'{o}n and Raquel Castelo-Branco and Shaurya Chanana and Alexander B Chase and Marc G Chevrette and Leticia V Costa-Lotufo and Jason M Crawford and Cameron R Currie and Bart Cuypers and Tam Dang and Tristan de Rond and Alyssa M Demko and Elke Dittmann and Chao Du and Christopher Drozd and Jean-Claude Dujardin and Rachel J Dutton and Anna Edlund and David P Fewer and Neha Garg and Julia M Gauglitz and Emily C Gentry and Lena Gerwick and Evgenia Glukhov and Harald Gross and Muriel Gugger and Dulce G Guill\'{e}n Matus and Eric J N Helfrich and Benjamin-Florian Hempel and Jae-Seoun Hur and Marianna Iorio and Paul R Jensen and Kyo Bin Kang and Leonard Kaysser and Neil L Kelleher and Chung Sub Kim and Ki Hyun Kim and Irina Koester and Gabriele M K\"{o}nig and Tiago Leao and Seoung Rak Lee and Yi-Yuan Lee and Xuanji Li and Jessica C Little and Katherine N Maloney and Daniel M\"{a}nnle and Christian Martin H. and Andrew C McAvoy and Willam W Metcalf and Hosein Mohimani and Carlos Molina-Santiago and Bradley S Moore and Michael W Mullowney and Mitchell Muskat and Louis-F\'{e}lix Nothias and Ellis C O'Neill and Elizabeth I Parkinson and Daniel Petras and J\"{o}rn Piel and Emily C Pierce and Karine Pires and Raphael Reher and Diego Romero and Caroline M Roper and Michael Rust and Hamada Saad and Carmen Saenz and Laura M Sanchez and S\oren Johannes S\orensen and Margherita Sosio and Roderich D S\"{u}ssmuth and Douglas Sweeney and Kapil Tahlan and Regan J Thomson and Nicholas J Tobias and Amaro E Trindade-Silva and Gilles P van Wezel and Mingxun Wang and Kelly C Weldon and Fan Zhang and Nadine Ziemert and Katherine R Duncan and Max Cr\"{u}semann and Simon Rogers and Pieter C Dorrestein and Marnix H Medema and Justin J J van der Hooft},

url = {https://doi.org/10.1038/s41589-020-00724-z},

doi = {10.1038/s41589-020-00724-z},

issn = {1552-4469},

year  = {2021},

date = {2021-02-15},

journal = {Nature Chemical Biology},

abstract = {Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{CUYPERS2018170,

title = {Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent},

author = {Bart Cuypers and Maya Berg and Hideo Imamura and Franck Dumetz and G\'{e}raldine [De Muylder] and Malgorzata A Domagalska and Suman Rijal and Narayan Raj Bhattarai and Ilse Maes and Mandy Sanders and James A Cotton and Pieter Meysman and Kris Laukens and Jean-Claude Dujardin},

url = {http://www.sciencedirect.com/science/article/pii/S1567134818302004},

doi = {https://doi.org/10.1016/j.meegid.2018.04.021},

issn = {1567-1348},

year  = {2018},

date = {2018-01-01},

journal = {Infection, Genetics and Evolution},

volume = {62},

pages = {170 - 178},

abstract = {Leishmania donovani is the responsible agent for visceral leishmaniasis (VL) in the Indian subcontinent (ISC). The disease is lethal without treatment and causes 0.2 to 0.4 million cases each year. Recently, reports of VL in Nepalese hilly districts have increased as well as VL cases caused by L. donovani from the ISC1 genetic group, a new and emerging genotype. In this study, we perform for the first time an integrated, untargeted genomics and metabolomics approach to characterize ISC1, in comparison with the Core Group (CG), main population that drove the most recent outbreak of VL in the ISC. We show that the ISC1 population is very different from the CG, both at genome and metabolome levels. The genomic differences include SNPs, CNV and small indels in genes coding for known virulence factors, immunogens and surface proteins. Both genomic and metabolic approaches highlighted dissimilarities related to membrane lipids, the nucleotide salvage pathway and the urea cycle in ISC1 versus CG. Many of these pathways and molecules are important for the interaction with the host/extracellular environment. Altogether, our data predict major functional differences in ISC1 versus CG parasites, including virulence. Therefore, particular attention is required to monitor the fate of this emerging ISC1 population in the ISC, especially in a post-VL elimination context.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Dumetze00548-17,

title = {Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent},

author = {F Dumetz and B Cuypers and H Imamura and D Zander and E D{textquoteright}Haenens and I Maes and M A Domagalska and J Clos and J -C Dujardin and G De Muylder},

editor = {Margaret Phillips},

url = {https://msphere.asm.org/content/3/2/e00548-17},

doi = {10.1128/mSphere.00548-17},

year  = {2018},

date = {2018-01-01},

journal = {mSphere},

volume = {3},

number = {2},

publisher = {American Society for Microbiology Journals},

abstract = {Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because of Leishmania donovani resistance, this drug offers a unique model for understanding drug resistance dynamics. In a previous phylogenomic study, we found two distinct populations of L. donovani: the core group (CG) in the Gangetic plains and ISC1 in the Nepalese highlands. Sb resistance was only encountered within the CG, and a series of potential markers were identified. Here, we analyzed the development of resistance to trivalent antimonials (SbIII) upon experimental selection in ISC1 and CG strains. We observed that (i) baseline SbIII susceptibility of parasites was higher in ISC1 than in the CG, (ii) time to SbIII resistance was higher for ISC1 parasites than for CG strains, and (iii) untargeted genomic and metabolomic analyses revealed molecular changes along the selection process: these were more numerous in ISC1 than in the CG. Altogether these observations led to the hypothesis that CG parasites are preadapted to SbIII resistance. This hypothesis was experimentally confirmed by showing that only wild-type CG strains could survive a direct exposure to the maximal concentration of SbIII. The main driver of this preadaptation was shown to be MRPA, a gene involved in SbIII sequestration and amplified in an intrachromosomal amplicon in all CG strains characterized so far. This amplicon emerged around 1850 in the CG, well before the implementation of antimonials for VL chemotherapy, and we discuss here several hypotheses of selective pressure that could have accompanied its emergence.IMPORTANCE The textquotedblleftantibiotic resistance crisistextquotedblright is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some Leishmania populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.1371/journal.pone.0180532,

title = {Macromolecular biosynthetic parameters and metabolic profile in different life stages of Leishmania braziliensis: Amastigotes as a functionally less active stage},

author = {Marlene Jara and Maya Berg and Guy Caljon and Geraldine de Muylder and Bart Cuypers and Denis Castillo and Ilse Maes and Mar\'{i}a Carmen del Orozco and Manu Vanaerschot and Jean-Claude Dujardin and Jorge Arevalo},

url = {https://doi.org/10.1371/journal.pone.0180532},

doi = {10.1371/journal.pone.0180532},

year  = {2017},

date = {2017-01-01},

journal = {PLOS ONE},

volume = {12},

number = {7},

pages = {1-22},

publisher = {Public Library of Science},

abstract = {It was recently hypothesized that Leishmania amastigotes could constitute a semi-quiescent stage characterized by low replication and reduced metabolic activity. This concept developed with Leishmania (Leishmania) mexicana and Leishmania (Leishmania) major models might explain numerous clinical and sub-clinical features of Leishmania (Viannia) braziliensis infections, like reactivation of the disease, non-response to chemotherapy or asymptomatic infections. We compared here in vitro the proliferative capability of L. (V.) braziliensis amastigotes and promastigotes, assessed the expression of key molecular parameters and performed metabolomic analysis. We found that contrary to the highly proliferative promastigotes, amastigotes (axenic and intracellular) do not show evidence of extensive proliferation. In parallel, amastigotes showed a significant decrease of (i) the kDNA mini-circle abundance, (ii) the intracellular ATP level, (iii) the ribosomal components: rRNA subunits 18S and 28S α and ribosomal proteins RPS15 and RPL19, (iv) total RNA and protein levels. An untargeted metabolomic study identified clear differences between the different life stages: in comparison to logarithmic promastigotes, axenic amastigotes showed (a) a strong decrease of 14 essential and non-essential amino acids and eight metabolites involved in polyamine synthesis, (b) extensive changes in the phospholipids composition and (c) increased levels of several endogenous and exogenous sterols. Altogether, our results show that L. (V.) braziliensis amastigotes can show a phenotype with negligible rate of proliferation, a lower capacity of biosynthesis, a reduced bio-energetic level and a strongly altered metabolism. Our results pave the way for further exploration of quiescence among amastigotes of this species.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Berg2242,

title = {Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations},

author = {Maya Berg and Raquel Garc{'i}a-Hern\'{a}ndez and Bart Cuypers and Manu Vanaerschot and Jos\'{e} I Manzano and Jos\'{e} A Poveda and Jos\'{e} A Ferragut and Santiago Castanys and Jean-Claude Dujardin and Francisco Gamarro},

url = {https://aac.asm.org/content/59/4/2242},

doi = {10.1128/AAC.04231-14},

issn = {0066-4804},

year  = {2015},

date = {2015-01-01},

journal = {Antimicrobial Agents and Chemotherapy},

volume = {59},

number = {4},

pages = {2242--2255},

publisher = {American Society for Microbiology Journals},

abstract = {Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL). In vitro, Leishmania donovani promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{BERG2013e201301002,

title = {LC-MS Metabolomics from study design to data-analysis \textendash using a versatile pathogen as a test case},

author = {Maya Berg and Manu Vanaerschot and Andris Jankevics and Bart Cuypers and Rainer Breitling and Jean-Claude Dujardin},

url = {http://www.sciencedirect.com/science/article/pii/S2001037014600453},

doi = {https://doi.org/10.5936/csbj.201301002},

issn = {2001-0370},

year  = {2013},

date = {2013-01-01},

journal = {Computational and Structural Biotechnology Journal},

volume = {4},

number = {5},

pages = {e201301002},

abstract = {Thanks to significant improvements in LC-MS technology, metabolomics is increasingly used as a tool to discriminate the responses of organisms to various stimuli or drugs. In this minireview we discuss all aspects of the LC-MS metabolomics pipeline, using a complex and versatile model organism, Leishmania donovani, as an illustrative example. The benefits of a hyphenated mass spectrometry platform and a detailed overview of the entire experimental pipeline from sampling, sample storage and sample list set-up to LC-MS measurements and the generation of meaningful results with state-of-the-art data-analysis software will be thoroughly discussed. Finally, we also highlight important pitfalls in the processing of LC-MS data and comment on the benefits of implementing metabolomics in a systems biology approach.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{doi:10.1111/mmi.12374,

title = {Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure},

author = {Maya Berg and Manu Vanaerschot and Andris Jankevics and Bart Cuypers and Ilse Maes and Sandip Mukherjee and Basudha Khanal and Suman Rijal and Syamal Roy and Fred Opperdoes and Rainer Breitling and Jean-Claude Dujardin},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/mmi.12374},

doi = {10.1111/mmi.12374},

year  = {2013},

date = {2013-01-01},

journal = {Molecular Microbiology},

volume = {90},

number = {2},

pages = {428-442},

abstract = {Summary Antimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG-resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC-MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L. donovani strains with a similar genetic background but different SSG-susceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG-resistant and SSG-sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG-resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG-resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG-resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under SbIII drug pressure.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}