USING PROTEIN STRUCTURE TO COMBAT ANTIMICROBIAL RESISTANCE
Grant number: 1174405 | Funding period: 2020 - 2021
The development & spread of antimicrobial resistance poses significant risks to human health. Sequencing offers enormous potential to manage this but understanding how & which mutations lead to resistance is challenging. This program will use the effects of mutations on the structure & function of proteins to pre-emptively identify resistance mutations. This information will be used to improve diagnosis of what drugs a pathogen is resistant to & in the development of resistance-resistant drugs.
Related publications (53)
Insights from Spatial Measures of Intolerance to Identifying Pathogenic Variants in Developmental and Epileptic Encephalopathies
Michael Silk, Alex de Sá, Moshe Olshansky, David B Ascher
<jats:p>Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that so..
A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism.
Shridhar Parthasarathy, Sarah McKeown Ruggiero, Antoinette Gelot, Fernanda C Soardi, Bethânia FR Ribeiro, Douglas EV Pires, David B Ascher, Alain Schmitt, Caroline Rambaud, Alfonso Represa, Hongbo M Xie, Laina Lusk, Olivia Wilmarth, Pamela Pojomovsky McDonnell, Olivia A Juarez, Alexandra N Grace, Julien Buratti, Cyril Mignot, Domitille Gras, Caroline Nava
Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) as a result of a dominant-negative..
A structural biology community assessment of AlphaFold2 applications.
Mehmet Akdel, Douglas EV Pires, Eduard Porta Pardo, Jürgen Jänes, Arthur O Zalevsky, Bálint Mészáros, Patrick Bryant, Lydia L Good, Roman A Laskowski, Gabriele Pozzati, Aditi Shenoy, Wensi Zhu, Petras Kundrotas, Victoria Ruiz Serra, Carlos HM Rodrigues, Alistair S Dunham, David Burke, Neera Borkakoti, Sameer Velankar, Adam Frost
Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recen..
kinCSM: Using graph-based signatures to predict small molecule CDK2 inhibitors
Yunzhuo Zhou, Raghad Al-Jarf, Azadeh Alavi, Thanh Binh Nguyen, Carlos HM Rodrigues, Douglas E Pires, David B Ascher
Protein phosphorylation acts as an essential on/off switch in many cellular signaling pathways. This has led to ongoing interest i..
cardioToxCSM: A Web Server for Predicting Cardiotoxicity of Small Molecules
Saba Iftkha, Alex GC de Sa, Joao PL Velloso, Raghad Aljarf, Douglas EV Pires, David B Ascher
The design of novel, safe, and effective drugs to treat human diseases is a challenging venture, with toxicity being one of the ma..
CSM-peptides: A computational approach to rapid identification of therapeutic peptides
Carlos HM Rodrigues, Anjali Garg, David Keizer, Douglas E Pires, David B Ascher
Peptides are attractive alternatives for the development of new therapeutic strategies due to their versatility and low complexity..
Identifying the molecular drivers of ALS-implicated missense mutations
Stephanie Portelli, Amanda Albanaz, Douglas Eduardo Valente Pires, David Benjamin Ascher
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressively fatal, neurodegenerative disease associated with both motor and..
HGDiscovery: An online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase
Malancha Karmakar, Vittoria Cicaloni, Carlos HM Rodrigues, Ottavia Spiga, Annalisa Santucci, David B Ascher
Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in the body. Affected..
VIVID A Web Application for Variant Interpretation and Visualization in Multi-dimensional Analyses
Swapnil Tichkule, Yoochan Myung, Myo T Naung, Brendan RE Ansell, Andrew J Guy, Namrata Srivastava, Somya Mehra, Simone M Caccio, Ivo Mueller, Alyssa E Barry, Cock van Oosterhout, Bernard Pope, David B Ascher, Aaron R Jex
Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA..
Evaluating hierarchical machine learning approaches to classify biological databases
Pamela M Rezende, Joicymara S Xavier, David B Ascher, Gabriel R Fernandes, Douglas E Pires
The rate of biological data generation has increased dramatically in recent years, which has driven the importance of databases as..
Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2.
Raghad Aljarf, Mengyuan Shen, Douglas EV Pires, David B Ascher
BRCA1 and BRCA2 are tumour suppressor genes that play a critical role in maintaining genomic stability via the DNA repair mechanis..
Systematic evaluation of computational tools to predict the effects of mutations on protein stability in the absence of experimental structures
Qisheng Pan, Thanh Binh Nguyen, David B Ascher, Douglas E Pires
Changes in protein sequence can have dramatic effects on how proteins fold, their stability and dynamics. Over the last 20 years, ..
Oxidative desulfurization pathway for complete catabolism of sulfoquinovose by bacteria
Mahima Sharma, James P Lingford, Marija Petricevic, Alexander JD Snow, Yunyang Zhang, Michael A Jarva, Janice W-Y Mui, Nichollas E Scott, Eleanor C Saunders, Ruwan Epa, Bruna M da Silva, Douglas EV Pires, David B Ascher, Malcolm J McConville, Gideon J Davies, Spencer J Williams, Ethan D Goddard-Borger
Catabolism of sulfoquinovose (SQ; 6-deoxy-6-sulfoglucose), the ubiquitous sulfosugar produced by photosynthetic organisms, is an i..
A bias of Asparagine to Lysine mutations in SARS-CoV-2 outside the receptor binding domain affects protein flexibility.
Jennifer C Boer, Qisheng Pan, Jessica K Holien, Thanh-Binh Nguyen, David B Ascher, Magdalena Plebanski
INTRODUCTION: COVID-19 pandemic has been threatening public health and economic development worldwide for over two years. Compared..
Bioinformatics Approaches to Predict Mutation Effects in the Binding Site of the Proangiogenic Molecule CD93.
Vittoria Cicaloni, Malancha Karmakar, Luisa Frusciante, Francesco Pettini, Anna Visibelli, Maurizio Orlandini, Federico Galvagni, Maurizio Mongiat, Michael Silk, Federica Nardi, David Ascher, Annalisa Santucci, Ottavia Spiga
The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multime..
mmCSM-NA: accurately predicting effects of single and multiple mutations on protein nucleic acid binding affinity
Binh Nguyen Thanh, Yoochan Myung, Alex GC de Sa, Douglas E Pires, David B Ascher
While protein-nucleic acid interactions are pivotal for many crucial biological processes, limited experimental data has made the ..
A novel deep intronic variant strongly associates with Alkaptonuria
Chien-Yi Lai, I-Jung Tsai, Pao-Chin Chiu, David B Ascher, Yin-Hsiu Chien, Yu-Hsuan Huang, Yi-Lin Lin, Wuh-Liang Hwu, Ni-Chung Lee
Alkaptonuria is a rare autosomal recessive inherited disorder of tyrosine metabolism, which causes ochronosis, arthropathy, cardia..
Structure-guided machine learning prediction of drug resistance mutations in Abelson 1 kinase
Yunzhuo Zhou, Stephanie Portelli, Megan Pat, Carlos HM Rodrigues, Nguyen Thanh-Binh, Douglas E Pires, David B Ascher
Kinases play crucial roles in cellular signalling and biological processes with their dysregulation associated with diseases, incl..
TSMDA: Target and symptom-based computational model for miRNA-disease-association prediction
Korawich Uthayopas, Alex GC de Sa, Azadeh Alavi, Douglas E Pires, David B Ascher
The emergence of high-throughput sequencing techniques has revealed a primary role of microRNAs (miRNAs) in a wide range of diseas..
Deep learning in diabetic foot ulcers detection: A comprehensive evaluation
Moi Hoon Yap, Ryo Hachiuma, Azadeh Alavi, Raphael Brungel, Bill Cassidy, Manu Goyal, Hongtao Zhu, Johannes Ruckert, Moshe Olshansky, Xiao Huang, Hideo Saito, Saeed Hassanpour, Christoph M Friedrich, David Ascher, Anping Song, Hiroki Kajita, David Gillespie, Neil D Reeves, Joseph Pappachan, Claire O'Shea
There has been a substantial amount of research involving computer methods and technology for the detection and recognition of dia..
pdCSM-cancer: Using Graph-Based Signatures to Identify Small Molecules with Anticancer Properties
Raghad Al-Jarf, Alex GC de Sa, Douglas E Pires, David B Ascher
The development of new, effective, and safe drugs to treat cancer remains a challenging and time-consuming task due to limited hit..
Definition of the immune evasion-replication interface of rabies virus P protein
Jingyu Zhan, Angela R Harrison, Stephanie Portelli, Thanh Binh Nguyen, Isshu Kojima, Siqiong Zheng, Fei Yan, Tatsunori Masatani, Stephen M Rawlinson, Ashish Sethi, Naoto Ito, David B Ascher, Gregory W Moseley, Paul R Gooley
Rabies virus phosphoprotein (P protein) is a multifunctional protein that plays key roles in replication as the polymerase cofacto..
The mutation G133D on Leishmania guyanensis AQP1 is highly destabilizing as revealed by molecular modeling and hypo-osmotic shock assay
Luiza G Tunes, David B Ascher, Douglas E Pires, Rubens L Monte-Neto
The Leishmania aquaglyceroporin 1 (AQP1) plays an important role in osmoregulation and antimony (Sb) uptake, being determinant for..
Assessing the performance of computational predictors for estimating protein stability changes upon missense mutations
Shahid Iqbal, Fuyi Li, Tatsuya Akutsu, David B Ascher, Geoffrey Webb, Jiangning Song
Understanding how a mutation might affect protein stability is of significant importance to protein engineering and for understand..
MTR3D: identifying regions within protein tertiary structures under purifying selection
Michael Silk, Douglas E Pires, Carlos HM Rodrigues, Elston N D'Souza, Moshe Olshansky, Natalie Thorne, David B Ascher
The identification of disease-causal variants is non-trivial. By mapping population variation from over 448,000 exome and genome s..
SAP domain forms a flexible part of DNA aperture in Ku70/80
Ales Hnizda, Petr Tesina, Thanh-Binh Nguyen, Zdenek Kukacka, Lukas Kater, Amanda Chaplin, Roland Beckmann, David B Ascher, Petr Novak, Tom L Blundell
Nonhomologous end joining (NHEJ) is a DNA repair mechanism that religates double-strand DNA breaks to maintain genomic integrity d..
Mercury methylation by metabolically versatile and cosmopolitan marine bacteria
Heyu Lin, David B Ascher, Yoochan Myung, Carl H Lamborg, Steven J Hallam, Caitlin M Gionfriddo, Kathryn E Holt, John W Moreau
Microbes transform aqueous mercury (Hg) into methylmercury (MeHg), a potent neurotoxin that accumulates in terrestrial and marine ..
ThermoMutDB: a thermodynamic database for missense mutations
Joicymara S Xavier, Nguyen Thanh-Binh, Malancha Karmarkar, Stephanie Portelli, Pamela M Rezende, Joao PL Velloso, David B Ascher, Douglas E Pires
Proteins are intricate, dynamic structures, and small changes in their amino acid sequences can lead to large effects on their fol..
Unveiling six potent and highly selective antileishmanial agents via the open source compound collection 'Pathogen Box' against antimony-sensitive and -resistant Leishmania braziliensis
Juliano A Souza Silva, Luiza G Tunes, Roney S Coimbra, David B Ascher, Douglas E Pires, Rubens L Monte-Neto
Despite all efforts to provide new chemical entities to tackle leishmaniases, we are still dependent on a the limited drug arsenal..
DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations
Carlos HM Rodrigues, Douglas EV Pires, David B Ascher
Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseas..
Structure guided prediction of Pyrazinamide resistance mutations in pncA
Malancha Karmakar, Carlos HM Rodrigues, Kristy Horan, Justin T Denholm, David B Ascher
Pyrazinamide plays an important role in tuberculosis treatment; however, its use is complicated by side-effects and challenges wit..
Combining structure and genomics to understand antimicrobial resistance
Tanushree Tunstall, Stephanie Portelli, Jody Phelan, Taane G Clark, David B Ascher, Nicholas Furnham
Antimicrobials against bacterial, viral and parasitic pathogens have transformed human and animal health. Nevertheless, their wide..
HARP: a database of structural impacts of systematic missense mutations in drug targets of Mycobacterium leprae
Sundeep Chaitanya Vedithi, Sony Malhotra, Marcin J Skwark, Asma Munir, Marta Acebron-Garcia-De-Eulate, Vaishali P Waman, Ali Alsulami, David B Ascher, Tom L Blundell
Computational Saturation Mutagenesis is an in-silico approach that employs systematic mutagenesis of each amino acid residue in th..