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Articles by Gerard Wright
The Caenorhabditis elegans microbiome impacts microsporidia infection through nutrient limitation and spore inactivation
Abstract Microsporidia are fungal parasites that can only reproduce inside the cells of a host, and they infect most animal groups, including humans and agriculturally important species. Animals also harbor a microbiome, which can shape resistance to infection, but the mechanisms by which bacteria influence microsporidia infection are poorly understood.
A natural depsipeptide antibiotic binds the E-site of the bacterial ribosome
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Abstract A key challenge in addressing the antibiotic resistance crisis is identifying new antimicrobial compounds1. Although natural products produced by fungi and bacteria, particularly actinomycetes, have been the source of most antibiotics discovered over the past 80 years, they have fallen out of favour owing to the frequent rediscovery of known drug scaffolds2. The current perception is that antibiotic-producing actinomycetes have been over-mined and possess little novelty left to yield.
By Manpreet Kaur, Dmitrii Y. Travin, Max Berger, Manoj Jangra, Martino Morici, Haaris A. Safdari, Dorota Klepacki, Wenliang Wang, Michael Cook, Sommer Chou, Allison K. Guitor, Kalinka Koteva, Min Xu, Linda Ejim, Aline A Fiebig, Brian K. Coombes, Lesley T. MacNeil, Nora Vázquez-Laslop, Alexander S. Mankin, Daniel Wilson, Gerard Wright, Yeganeh Yousefi
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Nature
Verified
Butyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi
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Keywords Cryptococcus Candida auris antifungal natural product fungal resistance flippase Apt1-Cdc50 synergy echinocandin butyrolactol A Get full text access Log in, subscribe or purchase for full access. References 1. Iliev, I.D. ∙ Brown, G.D. ∙ Bacher, P. ... Focus on fungi Cell. 2024; 187:5121-5127 2. Denning, D.W. Global incidence and mortality of severe fungal disease Lancet Infect. Dis. 2024; 24:e428-e438 3. Brown, G.D. ∙ Denning, D.W. ∙ Gow, N.A.R. ... Hidden Killers: Human Fungal Infections Sci.
By Xuefei Chen, H. Diessel Duan, Michael J Hoy, Kalinka Koteva, Michaela Spitzer, Allison K. Guitor, Emily Puumala, Aline A Fiebig, Guanggan Hu, Bonnie Yiu, Sommer Chou, Zhuyun Bian, Yeseul Choi, Wenliang Wang, Sheng Sun, Nicole Robbins, Anna Floyd Averette, Michael Cook, Ray Truant, Lesley T. MacNeil, Eric Brown, James W. Kronstad, Brian K. Coombes, Leah Cowen, Joseph Heitman, Huilin Li, Gerard Wright
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Cell Press
Verified
Fragment-based drug design of a bacterial kinase inhibitor capable of increasing the antibiotic sensitivity of clinical isolates - Communications Chemistry
Abstract According to the World Health Organization (WHO), antimicrobial resistance is a serious global health issue. Overcoming antibiotic resistance involves several strategies, including the inhibition of resistance mechanisms. Among the various resistance mechanisms, aminoglycoside phosphotransferases (APHs) catalyze the transfer of the γ-phosphate from a nucleotide donor to various aminoglycosides, leading to their inactivation.
Fungal impacts on Earth’s ecosystems - Nature
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Abstract Over the past billion years, the fungal kingdom has diversified to more than two million species, with over 95% still undescribed. Beyond the well-known macroscopic mushrooms and microscopic yeast, fungi are heterotrophs that feed on almost any organic carbon, recycling nutrients through the decay of dead plants and animals and sequestering carbon into Earth’s ecosystems.
By Sarah J. Gurr, Matthew Fisher, David Blehert, Charles Boone, Arturo Casadevall, Anuradha Chowdhary, Christina A. Cuomo, Iuliana V. Ene, Aleeza Gerstein, Asiya Gusa, Iliyan D. Iliev, Timothy James, Hailing Jin, Regine Kahmann, Kabir G. Peay, Rebecca Shapiro, Jason E. Stajich, John Taylor, Gerard Wright, Leah Cowen, Joseph Heitman
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Nature
Verified
The Comprehensive Antibiotic Resistance Database
Model Type: protein homolog model Model Definition: Protein Homolog Models (PHM) detect protein sequences based on their similarity to a curated reference sequence, using curated BLASTP bitscore cut-offs. Protein Homolog Models apply to all genes that confer resistance through their presence in an organism, such as the presence of a beta-lactamase gene on a plasmid. PHMs include a reference sequence and a bitscore cut-off for detection using BLASTP.
New strategies for combating multidrug-resistant bacteria
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HelR is a helicase-like protein that protects RNA polymerase from rifamycin antibiotics
Adams K.N. Takaki K. Connolly L.E. Wiedenhoft H. Winglee K. Humbert O. Edelstein P.H. Cosma C.L. Ramakrishnan L. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell. 2011; 145: 39-53https://doi.org/10.1016/j.cell.2011.02.022 Altschul S.F. Madden T.L. Schäffer A.A. Zhang J. Zhang Z. Miller W. Lipman D.J. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res.
Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation - Nature Communications
Abstract Fungal infections cause more than 1.5 million deaths annually. With an increase in immune-deficient susceptible populations and the emergence of antifungal drug resistance, there is an urgent need for novel strategies to combat these life-threatening infections. Here, we use a combinatorial screening approach to identify an imidazopyrazoindole, NPD827, that synergizes with fluconazole against azole-sensitive and -resistant isolates of Candida albicans.
Super Bowl LVI: David Hill applied lessons from Australian sport to revolutionise the coverage of NFL, EPL
David Hill learned from Rupert Murdoch, Kerry Packer and Ron Casey to transform US and UK sport coverage, writes GERARD WRIGHT. New Orleans, Sunday, February 3, 2002: There were the four living ex-presidents and Nancy Reagan, the sainted wife of the fifth - they provided the pre-game narration for the immortal piece performed by the Boston Pops Orchestra, on the playing field of the Superdome. It was Aaron Copland’s Lincoln Portrait, written in 1942 to soothe and inspire a nation under attack.
NHL Hockey | Nathan Walker, the 175cm Aussie icebreaker in a land of giants | CODE Sports
With a play as “simple as treading water while delivering stiff-arms to anyone in range”, Nathan Walker – Australia’s first NHL draftee – now truly belongs at ice hockey’s highest level. What’s wrong with this picture? The countries of origin in any given St Louis Blues line-up that turns out: United States, Sweden, Russia, Finland, Canada. And Australia.
NFL | The cold case murder of Colin Ridgway, the first ever Australian to play in the NFL
Colin Ridgway’s forgotten time in the public eye began on the Melbourne Cricket Ground in the mid-afternoon of November 23, 1956, and ended with an ambush inside the home he was soon to quit in Dallas in May, 1993. It began with him defying gravity and every expectation of his life and upbringing, and ended with him denying the unimaginable, up until the very moment it happened.
Aspergillomarasmine A inhibits metallo-β-lactamases by selectively sequestering Zn2+
Abstract Class B metallo-β-lactamases (MBLs) are Zn2+-dependent enzymes that catalyze the hydrolysis of β-lactam antibiotics to confer resistance in bacteria. Several problematic groups of MBLs belong to subclass B1, including the binuclear NDM, VIM, and IMP-type enzymes, which are responsible for widespread antibiotic resistance.
Structural Characterization of Diazabicyclooctane β-Lactam “Enhancers” in Complex with Penicillin-Binding Proteins PBP2 and PBP3 of Pseudomonas aeruginosa
Research Article | Therapeutics and Prevention Malligarjunan Rajavel, Vijay Kumar, Ha Nguyen, Jacob Wyatt, Steven H. Marshall, Krisztina M. Papp-Wallace, Prasad Deshpande, Satish Bhavsar, Ravindra Yeole, Sachin Bhagwat, Mahesh Patel, Robert A. Bonomo, Focco van den Akker Gerard D. Wright, Editor DOI: 10.1128/mBio.03058-20 ABSTRACT Multidrug-resistant (MDR) pathogens pose a significant public health threat.
Competition Sensing Changes Antibiotic Production in Streptomyces
Research Article | Ecological and Evolutionary Science Sanne Westhoff, Alexander M. Kloosterman, Stephan F. A. van Hoesel, Gilles P. van Wezel, Daniel E. Rozen Gerard D. Wright, Editor DOI: 10.1128/mBio.02729-20 ABSTRACT One of the most important ways that bacteria compete for resources and space is by producing antibiotics that inhibit competitors.
ApmA Is a Unique Aminoglycoside Antibiotic Acetyltransferase That Inactivates Apramycin
Research Article | Therapeutics and Prevention Emily Bordeleau, Peter J. Stogios, Elena Evdokimova, Kalinka Koteva, Alexei Savchenko, Gerard D. Wright Marcelo Tolmasky, Invited Editor, Karen Bush, Editor DOI: 10.1128/mBio.02705-20 ABSTRACT Apramycin is an aminoglycoside antibiotic with the potential to be developed to combat multidrug-resistant pathogens.
Cryptic or Silent? The Known Unknowns, Unknown Knowns, and Unknown Unknowns of Secondary Metabolism
Perspective | Applied and Environmental Science Paul A. Hoskisson, Ryan F. Seipke Gerard D. Wright, Editor DOI: 10.1128/mBio.02642-20 ABSTRACT Microbial natural products, particularly those produced by filamentous Actinobacteria, underpin the majority of clinically used antibiotics. Unfortunately, only a few new antibiotic classes have been discovered since the 1970s, which has exacerbated fears of a postapocalyptic world in which antibiotics have lost their utility.
Offloading Role of a Discrete Thioesterase in Type II Polyketide Biosynthesis
Research Article | Molecular Biology and Physiology Kangmin Hua, Xiangyang Liu, Yuchun Zhao, Yaojie Gao, Lifeng Pan, Haoran Zhang, Zixin Deng, Ming Jiang Barrie Wilkinson, Invited Editor, Gerard D. Wright, Editor DOI: 10.1128/mBio.01334-20 ABSTRACT Type II polyketides are a group of secondary metabolites with various biological activities.
Antibacterial drug discovery in the resistance era
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Antibiotic resistance: it’s bad, but why isn’t it worse?
Nicholas Waglechner1 & Gerard D. Wright1 BMC Biology volume 15, Article number: 84 (2017) Cite this article 14k Accesses 23 Citations 104 Altmetric Metrics details Abstract Antibiotic natural products are ancient and so is resistance. Consequently, environmental bacteria harbor numerous and varied antibiotic resistance elements. Nevertheless, despite long histories of antibiotic production and exposure, environmental bacteria are not resistant to all known antibiotics.
Suppression of β-Lactam Resistance by Aspergillomarasmine A Is Influenced by both the Metallo-β-Lactamase Target and the Antibiotic Partner
Editor's Pick Mechanisms of Resistance Caitlyn M. Rotondo, David Sychantha, Kalinka Koteva, Gerard D. Wright DOI: 10.1128/AAC.01386-19 ABSTRACT The rise of Gram-negative pathogens expressing metallo-β-lactamases (MBLs) is a growing concern, threatening the efficacy of β-lactam antibiotics, in particular, the carbapenems. There are no inhibitors of MBLs in current clinical use.
Perspective: Synthetic biology revives antibiotics
Re-engineering natural products provides a new route to drug discovery, says Gerard Wright. Credit: Mike Lalich The drug discovery process often involves natural products or compounds that are inspired by them and modified by medicinal chemistry. For example, acetylsalicylic acid (aspirin) is one of the first cases of a natural product being modified to improve its drug-like properties.
Membrane-Active Rhamnolipids Overcome Aminoglycoside Resistance
In this issue of Cell Chemical Biology, Radlinski et al. (2019) Radlinski L.C. Rowe S.E. Brzozowski R. Wilkinson A.D. Huang R. Eswara P. Conlon B.P. Chemical induction of aminoglycoside uptake overcomes antibiotic tolerance and resistance in Staphylococcus aureus. Cell Chem. Biol. 2019; 10.1016/j.chembiol.2019.07.009 identify Pseudomonas-derived rhamnolipids that potentiate aminoglycoside antibiotics in the eradication of antibiotic-tolerant bacterial phenotypes.
Hidden antibiotics in actinomycetes can be identified by inactivation of gene clusters for common antibiotics
Abstract Actinobacteria, which are one of the largest bacterial phyla and comprise between 13 and 30% of the soil microbiota, are the main source of antibiotic classes in clinical use1. During screens for antimicrobials, as many as 50% of actinomycete strains are discarded because they produce a known antibiotic (Supplementary Fig. 1) (ref. 2).
Drug combinations: a strategy to extend the life of antibiotics in the 21st century
Abstract Antimicrobial resistance threatens a resurgence of life-threatening bacterial infections and the potential demise of many aspects of modern medicine. Despite intensive drug discovery efforts, no new classes of antibiotics have been developed into new medicines for decades, in large part owing to the stringent chemical, biological and pharmacological requisites for effective antibiotic drugs.
Trichlorination of a Teicoplanin-Type Glycopeptide Antibiotic by the Halogenase StaI Evades Resistance
ABSTRACT Glycopeptide antibiotics (GPAs) include clinically important drugs used for the treatment of infections caused by Gram-positive pathogens. These antibiotics are specialized metabolites produced by several genera of actinomycete bacteria. While many GPAs are highly chemically modified, A47934 is a relatively unadorned GPA lacking sugar or acyl modifications, common to other members of the class, but which is chlorinated at three distinct sites.
Death penalty dilemma: Debate on Props. 62 and 66 hits cost
Money changes everything, it is said, and that adage hovers conspicuously over two clashing death penalty proposals that Californians will weigh in next week’s election. Proposition 62 asks voters to abolish the state’s death penalty after 38 years. The other measure, Proposition 66, promotes a streamlining of legal proceedings so the term “capital punishment” means what it says.
Catalytic promiscuity of glycopeptide N-methyltransferases enables bio-orthogonal labelling of biosynthetic intermediates
We show that two ?-N-methyltransferases involved in the biosynthesis of glycopeptide antibiotics (GPAs) already recognise partly crosslinked precursor peptides of teicoplanin aglycone indicating that in vivo N-methylation can occur as an early tailoring step during GPA biosynthesis.
The Fastest Woman On Two Wheels
For five minutes, the vortex will be home. It’s the retreat from the outside world, where the wind roars in from three different directions, where the salted ground passes inches below, at 150 mph, and a type of immortality beckons.
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