Lorne Taylor

McGill University Health Centre

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Marcel A. Behr

McGill University

Andréanne Lupien

McGill University Health Centre

Jaryd R. Sullivan

McGill University

Donald J. van Meyel

McGill University

Sejal Davla

McGill University

Ari Gritsas

McGill University Health Centre

Jenn Nedow

McGill University Health Centre

Edward Daly

McGill University Health Centre

Ori Solomon

Sydney Local Health District

Kim Munro

University of South Australia

Cooperative Institutions

McGill University

McGill University Health Centre

Montreal Neurological Institute and Hospital

University of Sydney

Structural Genomics Consortium

Douglas Mental Health University Institute

Montreal General Hospital

Drug Discovery Laboratory (Norway)

Université de Montréal

Johns Hopkins University

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A rapid and reliable multiplexed LC-MS/MS method for simultaneous analysis of six monoamines from brain tissues

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Sejal Davla Edward Daly Jenn Nedow Ari Gritsas Laura Curran

Abstract Monoamines are a class of neuromodulators that are crucial for a variety of brain functions, including control of mood, movement, sleep and cognition. From mammals to insects, the nervous system is enriched in monoamines such as dopamine, serotonin and melatonin, analytes which range from being highly polar to non-polar. Here we developed a method using liquid chromatography coupled with mass spectrometry (LC-MS) to quantify in a single run the amounts of six distinct monoamines in extracts from dissected Drosophila and mouse brain tissues. The measured monoamines were dopamine (DA), serotonin (also known as 5-hydroxytryptamine (5-HT)), octopamine (OA, an insect equivalent of norepinephrine), tyramine (TA), melatonin (MT) and N-acetyl-hydroxy-serotonin (NAS). The analytical range of these monoamines was between 0.25 to 5.0 ng/mL.

Octopamine (neurotransmitter)

Tyramine

10.1101/2021.05.24.445477

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Citations (0)

Loss of allosteric regulation in α-isopropylmalate synthase identified as an antimicrobial resistance mechanism

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Jaryd R. Sullivan Christophe Courtine Lorne Taylor Ori Solomon Marcel A. Behr

Abstract Despite our best efforts to discover new antimicrobials, bacteria have evolved mechanisms to become resistant. Resistance to antimicrobials can be attributed to innate, inducible, and acquired mechanisms. Mycobacterium abscessus is one of the most antimicrobial resistant bacteria and is known to cause chronic pulmonary infections within the cystic fibrosis community. Previously, we identified epetraborole as an inhibitor against M. abscessus with in vitro and in vivo activities and that the efficacy of epetraborole could be improved with the combination of the non-proteinogenic amino acid norvaline. Norvaline demonstrated activity against the M. abscessus epetraborole resistant mutants thus, limiting resistance to epetraborole in wild type populations. Here we show M. abscessus mutants with resistance to epetraborole can acquire resistance to norvaline in a leucyl-tRNA synthetase (LeuRS) editing-independent manner. After showing that the membrane hydrophobicity and efflux activity are not linked to norvaline resistance, whole-genome sequencing identified a mutation in the allosteric regulatory domain of α-isopropylmalate synthase (α-IPMS). We found that mutants with the α-IPMS A555V variant incorporated less norvaline in the proteome and produced more leucine than the parental strain. Furthermore, we found that leucine can rescue growth inhibition from norvaline challenge in the parental strain. Our results demonstrate that M. abscessus can modulate its metabolism through mutations in an allosteric regulatory site to upregulate the biosynthesis of the natural LeuRS substrate and outcompete norvaline. These findings emphasize the antimicrobial resistant nature of M. abscessus and describe a unique mechanism of substrate-inhibitor competition. Significance Statement Cystic fibrosis patients and individuals undergoing plastic surgery are at risk for acquiring chronic infections from Mycobacterium abscessus . Current antibiotics are not adequate and require increased drug discovery efforts to identify better treatments for these patients. The benzoxaborole, epetraborole has been shown by our group and others to be a promising candidate against M. abscessus but the emergence of resistance to epetraborole in a clinical trial for complicated urinary tract infections has hindered its development. Previously, we identified the combination of epetraborole and norvaline as a potential means to limit resistance against epetraborole. Our results here demonstrate that M. abscessus can acquire resistance to both epetraborole and norvaline. These results may help develop combination therapies to reduce the risk of resistance to benzoxaboroles and non-proteinogenic amino acids.

Norvaline

Efflux

10.1101/2022.12.07.519492

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Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Jaryd R. Sullivan Andréanne Lupien Elias Kalthoff Claire Hamela Lorne Taylor

Abstract Certain aminoacyl-tRNA synthetases developed a proofreading mechanism to ensure aminoacylation of tRNAs with cognate amino acids. Epetraborole (EPT) was identified as an inhibitor of the leucyl-tRNA synthetase (LeuRS) editing site in Mycobacterium abscessus . EPT displayed enhanced activity against M. abscessus over Mycobacterium tuberculosis . Crystallographic and equilibrium binding data showed that EPT binds LeuRS Mabs and LeuRS Mtb with similar Kd. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed the non-proteinogenic amino acid norvaline, leucine residues in proteins were replaced by norvaline, inducing expression of GroEL chaperonins and Clp proteases. In vitro data revealed that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis . The combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection.

Norvaline

Mycobacterium abscessus

Aminoacylation

10.1101/2021.06.01.446617

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Citations (3)

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

PLoS Pathogens (2021)

Jaryd R. Sullivan Andréanne Lupien Elias Kalthoff Claire Hamela Lorne Taylor

Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M . abscessus displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarithromycin. As such, M . abscessus is clinically resistant to the entire regimen of front-line M . tuberculosis drugs, and treatment with antibiotics that do inhibit M . abscessus in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in M . abscessus . EPT protected zebrafish from lethal M . abscessus infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against M . abscessus than M . tuberculosis , but crystallographic and equilibrium binding data showed that EPT binds LeuRS Mabs and LeuRS Mtb with similar residues and dissociation constants. Since EPT-resistant M . abscessus mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when M . abscessus LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our in vitro data that supplementation of media with norvaline reduced the emergence of EPT mutants in both M . abscessus and M . tuberculosis . Furthermore, the combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M . abscessus infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen M . abscessus , and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for M . abscessus and other mycobacterial infections like tuberculosis.

Mycobacterium abscessus

Norvaline

10.1371/journal.ppat.1009965

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Citations (31)

Loss of allosteric regulation in α-isopropylmalate synthase identified as an antimicrobial resistance mechanism

npj Antimicrobials and Resistance (2023)

Jaryd R. Sullivan Christophe Courtine Lorne Taylor Ori Solomon Marcel A. Behr

Norvaline

Efflux

10.1038/s44259-023-00005-4

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Citations (1)

An approach to measuring protein turnover in human induced pluripotent stem cell organoids by mass spectrometry

Methods (2022)

Jing Dong Anthony Duchesne Andrew N. Bayne Nguyen‐Vi Mohamed Wei Yi

Organoid

Proteostasis

Cell type

Protein turnover

10.1016/j.ymeth.2022.03.011

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Citations (9)

An LC-MS/MS method for simultaneous analysis of up to six monoamines from brain tissues

Journal of Chromatography B (2023)

Sejal Davla Edward Daly Jenn Nedow Ari Gritsas Laura Curran

Monoamines are a class of neuromodulators that are crucial for a variety of brain functions, including control of mood, movement, sleep and cognition. From mammals to insects, the nervous system is enriched in monoamines such as dopamine, serotonin and melatonin, analytes which range from being highly polar to non-polar. Here we developed a method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify in a single run the amounts of six distinct monoamines in extracts from dissected Drosophila and mouse brain tissues. The measured monoamines were dopamine (DA), serotonin (also known as 5-hydroxytryptamine (5-HT)), octopamine (OA, an insect equivalent of norepinephrine), tyramine (TA), melatonin (MT) and N-acetylserotonin (NAS). The analytical range of these monoamines was between 0.25 and 5.0 ng/mL. This quantitative LC-MS/MS methodology has important use for simultaneous measurement of distinct neuroactive monoamines from precious biological specimens.

Octopamine (neurotransmitter)

Tyramine

Monoaminergic

10.1016/j.jchromb.2023.123604

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Citations (7)

M. orygis hypervirulence provides new insights into tuberculosis pathogenesis

Research Square (Research Square) (2024)

Marcel A. Behr Sarah N Danchuk Shannon C Duffy Jaryd R. Sullivan Syed Beenish Rufai

Abstract The Mycobacterium tuberculosis complex (MTBC) includes M. tuberculosis (M. tb), the cause of human tuberculosis, and the animal pathogens, M. bovis and M. orygis, causes of tuberculosis in a broad range of mammalian hosts, including humans. Since the late 1800s, M. tb and M. bovis have shown distinct differences in clinical presentation and virulence following experimental infection. However, the pathogenicity of M. orygis has yet to be subject to experimental investigation. Despite possessing the smallest genome of the three, M. orygis is hypervirulent in C57BL/6 mice, comparable to M. bovis, but markedly different from M. tb. Proteomic comparisons, gene disruptions and infection studies reinforced the importance of the canonical virulence factor, ESAT-6, and identified MPT70 as a non-canonical virulence factor. The demonstration of differential virulence among these MTBC lineages necessitates a reconsideration of M. tb as the default organism for pathogenesis studies and has fundamental and translational implications for tuberculosis research.

Pathogenesis

10.21203/rs.3.rs-3911791/v1

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Unraveling the Relevance of Tissue‐Specific Decellularized Extracellular Matrix Hydrogels for Vocal Fold Regenerative Biomaterials: A Comprehensive Proteomic and In Vitro Study

Advanced NanoBiomed Research (2023)

Mika Brown Shirley Zhu Lorne Taylor Maryam Tabrizian Nicole Y. K. Li‐Jessen

Decellularized extracellular matrix (dECM) is a promising material for tissue engineering applications. Tissue‐specific dECM is seen as a favorable material that recapitulates a native‐like microenvironment for cellular remodeling. However, the minute quantity of dECM derivable from small organs like the vocal fold (VF) hampers manufacturing scalability. Small intestinal submucosa (SIS), a commercial product with proven regenerative capacity, may be a viable option for VF applications. This study aims to compare SIS and VF dECM hydrogels with respect to protein content and functionality using mass spectrometry‐based proteomics and in vitro studies. Proteomic analysis reveals that VF and SIS dECM share 75% of core matrisome proteins. Although VF dECM proteins have greater overlap with native VF, SIS dECM shows less cross‐sample variability. Following decellularization, significant reductions of soluble collagen (61%), elastin (81%), and hyaluronan (44%) are noted in VF dECM. SIS dECM contains comparable elastin and hyaluronan but 67% greater soluble collagen than VF dECM. Cells deposit more neo‐collagen on SIS than VF‐dECM hydrogels, but comparable neo‐elastin (≈50 μg scaffold −1 ) and neo‐hyaluronan (≈6 μg scaffold −1 ). Overall, SIS dECM possesses a reasonably similar proteomic profile and regenerative capacity to VF dECM. SIS dECM is a promising alternative for dECM‐derived biomaterials for VF regeneration.

Decellularization

Regenerative Medicine

10.1002/anbr.202200095

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Citations (3)

Altered Proteomics in Brain Extracellular Vesicles from Depressed Individuals Who Died by Suicide Implicates Synaptic Processes

The International Journal of Neuropsychopharmacology (2025)

Pascal Ibrahim Haruka Mitsuhashi Lorne Taylor Jenna Cleyle Naguib Mechawar

Abstract Background Major Depressive Disorder (MDD) is a common and debilitating disorder whose molecular neurobiology remains unclear. Extracellular vesicles (EVs) are small vesicles that are released by cells and are involved in intercellular communication. They carry bioactive molecules, such as proteins, that reflect the state of their cell of origin. In this study, we sought to investigate the proteomic cargo of brain EVs from depressed individuals as compared to EVs from matched neurotypical individuals. In addition, we investigated how the EV proteomic cargo compares to the proteomic profile of bulk tissue. Methods Using mass spectrometry and label-free quantification (LFQ), we investigated the EV and bulk tissue protein profile from anterior cingulate cortex (ACC) samples from 86 individuals. We performed differential expression analysis to compare cases and controls, followed by in silico analysis to determine potential implicated functions of dysregulated proteins. Results EVs display distinct proteomic profiles compared to bulk tissue. Differential expression analysis showed that 70 proteins were differentially packaged in EVs in MDD, while there was no significant difference in protein levels between groups in bulk tissue. In silico analysis points to a strong role of these differential EV proteins in synaptic functions. Conclusion To our knowledge, this is the first study to profile EV proteins in depression, providing novel information to better understand the pathophysiology of MDD. This work paves the way for discovering new therapeutic targets for MDD and prompts more investigations into EVs in MDD and other psychiatric disorders.

Proteome

10.1093/ijnp/pyaf012

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Citations (0)