Featured
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Article
| Open AccessStructure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir
In this study, the authors report the structure-based discovery and preclinical evaluation of 2 simnotrelvir, an orally bioavailable 3CLpro inhibitor that blocks replication of SARS-CoV-2 variants in 3 vitro, shows robust efficacy in a mouse model and good safety and pharmacokinetic profiles in rats 4 and monkeys.
- Xiangrui Jiang
- , Haixia Su
- & Yechun Xu
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Article
| Open AccessClinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito
Malaria parasites from patients who fail atovaquone therapies are highly drug-resistant, with mutations at Y268 in cytochrome b. Here the authors show that this mutation results in multiple defects in the parasite’s development and prevents transmission from mosquitoes to mice.
- Victoria A. Balta
- , Deborah Stiffler
- & Theresa A. Shapiro
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Article
| Open AccessA human monoclonal antibody binds within the poliovirus receptor-binding site to neutralize all three serotypes
Cross-neutralizing activity of monoclonal antibodies against poliovirus serotypes is less commonly reported. In this study, the authors use high-resolution cryo-EM to reveal that a cross-neutralizing human antibody neutralizes all three poliovirus serotypes by interacting with the receptor-binding region, called the canyon.
- Andrew J. Charnesky
- , Julia E. Faust
- & Susan L. Hafenstein
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Article
| Open AccessDeep mutational scanning reveals the molecular determinants of RNA polymerase-mediated adaptation and tradeoffs
Mutations in an RNA polymerase fragment, frequently found in lab adaptation, cluster in two modules favoring growth or maintenance via loss of interactions. Combining mutations in both modules enhances both traits, promoting compensatory evolution.
- Alaksh Choudhury
- , Benoit Gachet
- & Olivier Tenaillon
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Perspective
| Open AccessThe uncertain role of substandard and falsified medicines in the emergence and spread of antimicrobial resistance
Substandard and falsified medicines are a problem, particularly in low- and middle-income countries, and effects on antimicrobial resistance development aren’t well understood. Here, the authors discuss mechanisms by which they can increase or decrease levels of resistance and the need for improved data collection and analytical approaches.
- Sean Cavany
- , Stella Nanyonga
- & Ben S. Cooper
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Article
| Open AccessHigh-throughput screening of BAM inhibitors in native membrane environment
The bacterial insertase BAM is a key target for novel antibiotics that are urgently needed. Here, we describe the implementation of an assay that allows screening for BAM inhibitors in the native membrane in high-throughput format.
- Parthasarathi Rath
- , Adrian Hermann
- & Sebastian Hiller
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Article
| Open AccessMultifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses
There are currently no treatment options for infection with Rift Valley fever virus (RVFV). Here, Chapman et al., show that a combination of human monoclonal antibodies targeting two different steps in early virus cell entry enhances protection in a mouse model and is effective at low doses.
- Nathaniel S. Chapman
- , Ruben J. G. Hulswit
- & James E. Crowe Jr.
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Article
| Open AccessBacterial motility can govern the dynamics of antibiotic resistance evolution
In nature, bacteria experience gradients of antibiotics, but we know little about how such heterogeneity affects bacterial adaptation. Piskovsky and Oliveira develop quantitative models of bacterial adaptation in antibiotic landscapes and find that bacterial motility can govern the spatiotemporal dynamics of antibiotic resistance evolution.
- Vit Piskovsky
- & Nuno M. Oliveira
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Article
| Open AccessMetallo-sideromycin as a dual functional complex for combating antimicrobial resistance
Here, the authors utilise cefiderocol, a sideromycin, in complex with colloidal bismuth citrate, to demonstrate antimicrobial efficacy against Pseudomonas aeruginosa in vivo.
- Chenyuan Wang
- , Yushan Xia
- & Hongzhe Sun
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Article
| Open AccessAn IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants
In this study, the authors report the development of an inhalable IgM-like ACE2 and show that it broadly neutralizes SARS-CoV-2 variants, lowers viral loads and lung pathology in hamsters when administered early, and has good safety profiles in rats and monkeys.
- Juan Liu
- , Fengfeng Mao
- & Wenhui Li
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Article
| Open AccessAntibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites
Broad-spectrum antibiotics can kill harmless bacteria in our intestine, thus facilitating invasion by antibiotic-resistant bacteria such as carbapenem-resistant Enterobacteriaceae (CRE). Here, Yip et al. show that killing gut bacteria with antibiotics leads to enrichment of nutrients and depletion of inhibitory microbial metabolites, which overall potentiates CRE growth.
- Alexander Y. G. Yip
- , Olivia G. King
- & Julie A. K. McDonald
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Matters Arising
| Open AccessAntibiotics and hexagonal order in the bacterial outer membrane
- Georgina Benn
- , Thomas J. Silhavy
- & Bart W. Hoogenboom
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Article
| Open AccessProfiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
The bacterial pathogen Burkholderia cenocepacia and related species are often multidrug resistant because their cell envelope restricts antibiotic penetration. Here, Hogan et al systematically identify genes associated with resistance and susceptibility to cell envelope-targeting antibiotics, providing insights into underlying mechanisms and suggesting avenues for development of improved antibacterial therapies.
- Andrew M. Hogan
- , A. S. M. Zisanur Rahman
- & Silvia T. Cardona
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Article
| Open AccessEngineered reporter phages for detection of Escherichia coli, Enterococcus, and Klebsiella in urine
Although diagnosis of urinary tract infections has improved through the use of point-of-care molecular technologies, they are however limited by poor specificity and / or sensitivity, and requirement of laboratory resources. In this work, the authors develop a bacteriophage-based diagnostic assay for the detection of prevalent uropathogens.
- Susanne Meile
- , Jiemin Du
- & Samuel Kilcher
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Article
| Open AccessConformational restriction shapes the inhibition of a multidrug efflux adaptor protein
Multidrug efflux protein pumps are key players in bacterial antimicrobial resistance. Here, the authors show how dynamics of a periplasmic pump component can be targeted for efflux inhibition.
- Benjamin Russell Lewis
- , Muhammad R. Uddin
- & Eamonn Reading
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Article
| Open AccessMolecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5
Penicillin Binding Proteins (PBPs) are the main targets of β-lactam antibiotics. Here the authors use NMR spectroscopy, crystallography and microbiology to define the dynamics of E. faecium PBP5 in solution and show that increased acyl-enzyme hydrolysis correlates with increased resistance.
- Yamanappa Hunashal
- , Ganesan Senthil Kumar
- & Wolfgang Peti
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Article
| Open AccessIn vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir
Ensitrelvir is an oral antiviral agent that targets SARS-CoV-2 and is clinically useful against infection with omicron variants. The authors characterized mutant viruses with reduced sensitivity to ensitrelvir in vitro and in vivo.
- Maki Kiso
- , Seiya Yamayoshi
- & Yoshihiro Kawaoka
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Article
| Open AccessStructural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A
The authors discovered that hygromycin A not only enhances the cell-killing properties of macrolides but also renders them active against resistant bacteria. The provided structures of antibiotic pairs in complex with WT and macrolide-resistant ribosomes rationalize binding cooperativity of these drugs.
- Chih-Wei Chen
- , Nadja Leimer
- & Maxim S. Svetlov
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Article
| Open AccessDecoding a cryptic mechanism of metronidazole resistance among globally disseminated fluoroquinolone-resistant Clostridioides difficile
Detection of resistance to the antibiotic metronidazole in C. difficile often requires the presence of heme in the media, for unclear reasons. Here, the authors show that most metronidazole-resistant strains carry a mutation that promotes expression of a heme-dependent enzyme that degrades nitroimidazoles, and the mutation often co-occurs with an amino-acid substitution in DNA gyrase that confers resistance to another class of antibiotics, fluoroquinolones.
- Abiola O. Olaitan
- , Chetna Dureja
- & Julian G. Hurdle
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Article
| Open AccessMixed strain pathogen populations accelerate the evolution of antibiotic resistance in patients
Here, Caballero et al. provide an in depth characterisation of patients colonized with single or mixed strains of Pseudomonas aeruginosa to demonstrate the impact of within-host diversity on the development of antibiotic resistance.
- Julio Diaz Caballero
- , Rachel M. Wheatley
- & R. Craig MacLean
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Article
| Open AccessOn the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis
Inhibition of bacterial cell wall synthesis by β-lactam antibiotics results in a loss of cell wall integrity, but cells die via a combination of downstream events involving metabolic perturbations and oxidative damage. Here, Kawai et al. identify key enzymatic steps that stimulate the generation of reactive oxygen species and highlight the role of iron homeostasis in the lethal effects mediated by oxidative damage.
- Yoshikazu Kawai
- , Maki Kawai
- & Jeff Errington
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Article
| Open AccessLateral membrane organization as target of an antimicrobial peptidomimetic compound
The mechanism of action of the antibacterial tripeptide AMC-109 is unclear. Here, Melcrová et al. show that AMC-109 self-assembles into stable aggregates with a cationic surface, and then individual peptides insert into the bacterial membrane and disrupt membrane nanodomains, thus affecting membrane function without forming pores.
- Adéla Melcrová
- , Sourav Maity
- & Wouter H. Roos
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Article
| Open AccessMolecular mechanism of plasmid-borne resistance to sulfonamide antibiotics
Bacterial resistance to sulfonamide antibiotics (sulfas) is mediated by acquisition of sul genes, which encode sulfa-insensitive versions of the target enzyme, dihydropteroate synthase. Here, Venkatesan et al. study Sul enzymes using biochemical, structural, mutational and functional analyses, revealing the molecular basis for Sul-mediated drug resistance.
- Meenakshi Venkatesan
- , Michael Fruci
- & Alexei Savchenko
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Article
| Open AccessArchitecture of a complete Bce-type antimicrobial peptide resistance module
Here the authors present cryo-EM structures of the Bacillus subtilis bacitracin resistance module BceABS, providing insight into the assembly and conformational dynamics within the complex, and coregulation between individual protein components.
- Natasha L. George
- & Benjamin J. Orlando
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Article
| Open AccessRegulation of the macrolide resistance ABC-F translation factor MsrD
Antibiotic resistance ABC-F factors protect the ribosome from important antibiotics. Here, for one of them, the authors describe its molecular regulation that involves ribosome stalling by antibiotics for which the factor provides resistance.
- Corentin R. Fostier
- , Farès Ousalem
- & Grégory Boël
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Article
| Open AccessDprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
Pretomanid and delamanid are pro-drugs used for the treatment of tuberculosis, but their precise mechanisms of action are unclear. Here, the authors identify an enzyme required for the synthesis of the mycobacterial cell wall as a molecular target of the activated drugs.
- Katherine A. Abrahams
- , Sarah M. Batt
- & Gurdyal S. Besra
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Article
| Open AccessMycobacterium abscessus VapC5 toxin potentiates evasion of antibiotic killing by ribosome overproduction and activation of multiple resistance pathways
Mycobacterium abscessus (Mab) infections are difficult to clear with antibiotics. Here the authors show that clinical Mab strains can acquire a toxin-antitoxin system that enhances survival upon treatment with current first-line antibiotics through depletion of tRNASerCGA and subsequent ribosome overproduction.
- Eduardo A. Troian
- , Heather M. Maldonado
- & Nancy A. Woychik
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Article
| Open AccessTrispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections
One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure.
- Wanwisa Promsote
- , Ling Xu
- & Richard A. Koup
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Article
| Open AccessMultivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2
There are currently two types of antiviral drugs – neutralizing antibodies and small molecule inhibitors. Here, the authors report the development of bicyclic peptides that combine the advantages of both and show their antiviral capacity against SARS-CoV-2 in vitro as well as in small animal models.
- Katherine U. Gaynor
- , Marina Vaysburd
- & Leo C. James
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Article
| Open AccessTiming of antibiotic administration determines the spread of plasmid-encoded antibiotic resistance during microbial range expansion
Plasmids are the main vector by which antibiotic resistance is transferred between bacterial cells within surface-associated communities. Here, Ma et al. show that plasmid spread peaks at intermediate antibiotic administration times, when the intermixing of plasmid donors and potential recipients is maximal.
- Yinyin Ma
- , Josep Ramoneda
- & David R. Johnson
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Article
| Open AccessA global genomic analysis of Salmonella Concord reveals lineages with high antimicrobial resistance in Ethiopia
Authors carry out a longitudinal genomic analysis of Salmonella enterica serovar Concord isolates from various geographical locations, to reconstruct population diversity, evolution and antimicrobial resistance distribution.
- Wim L. Cuypers
- , Pieter Meysman
- & Sandra Van Puyvelde
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Article
| Open AccessEfflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic
Antibiotics that attack multiple targets in bacteria are thought to reduce the frequency of resistance. The authors show that genomic amplifications of poorly characterized efflux pumps can instead lead to high-frequency antibiotic cross-resistance.
- Kalinga Pavan T. Silva
- , Ganesh Sundar
- & Anupama Khare
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Article
| Open AccessA first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi
Hsp110 chaperones play important roles in protein homeostasis in eukaryotes. Here, the authors identify a small compound that inhibits fungal Hsp110s as well as the growth and viability of the pathogenic fungus Candida albicans, supporting Hsp110s as targets for development of new antifungal drugs.
- Liqing Hu
- , Cancan Sun
- & Qinglian Liu
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Article
| Open AccessA point mutation in recC associated with subclonal replacement of carbapenem-resistant Klebsiella pneumoniae ST11 in China
Authors carry out a genomic analysis of carbapenem-resistant Klebsiella pneumoniae bloodstream isolates, noting subclonal expansion, associated with the emergence of a hypervirulent subpopulation.
- Kai Zhou
- , Chun-Xu Xue
- & Yonghong Xiao
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Article
| Open AccessTranscription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing
Antibiotic resistance in Staphylococcus aureus is increasingly emerging. Here, Shu et al demonstrate that transcriptional regulation by S-nitrosylation underlies vancomycin resistance.
- Xueqin Shu
- , Yingying Shi
- & Baolin Sun
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Article
| Open AccessNirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in female Syrian hamsters and retains partial susceptibility to treatment
Characteristics of drug-resistant SARS-CoV-2 viruses are unclear. Here, the authors report that an in vitro selected nirmatrelvir-resistant virus replicates efficiently and can be transmitted in Syrian hamsters but that nirmatrelvir retains some antiviral activity against that virus in infected hamsters.
- Rana Abdelnabi
- , Dirk Jochmans
- & Johan Neyts
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Article
| Open AccessA host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi
Current treatment of fungal infections is threatened by emerging antifungal drug resistance. In this work, the authors explore the synergistic activity of a host defense peptide mimetic, brilacidin, with caspofungin against a panel of fungal strains.
- Thaila Fernanda dos Reis
- , Patrícia Alves de Castro
- & Gustavo H. Goldman
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Article
| Open AccessAssociate toxin-antitoxin with CRISPR-Cas to kill multidrug-resistant pathogens
CRISPR-regulated toxin-antitoxin (CreTA), safeguards CRISPR-Cas immune systems. Here the authors characterize a bacterial CreTA and use this to generate a proof-of-concept antimicrobial strategy, ATTACK, which associates TA and CRISPR-Cas to kill multidrug resistant pathogens.
- Rui Wang
- , Xian Shu
- & Ming Li
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Article
| Open AccessCollateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance
Collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities for antimicrobial drug discovery. Here, Liu et al. screen large chemical libraries across 29 drug-resistant E. coli strains to identify multiple CS interactions, including natural products with potent CS activities against cephalosporin-resistant strains.
- Dennis Y. Liu
- , Laura Phillips
- & Roger G. Linington
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Article
| Open AccessThe relative transmission fitness of multidrug-resistant Mycobacterium tuberculosis in a drug resistance hotspot
Geographical hotspots with high frequency of multi-drug resistant tuberculosis (MDR-TB) have been observed in several locations, such as the country of Georgia. Here, the authors analyse genomic sequences from tuberculosis bacteria isolated from Georgia to show that the transmission fitness of MDR-TB strains is heterogeneous, and highly drug-resistant and transmissible isolates contribute to the emergence and maintenance of MDR-TB hotspots.
- Chloé Loiseau
- , Etthel M. Windels
- & Sebastien Gagneux
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Article
| Open AccessThe F-pilus biomechanical adaptability accelerates conjugative dissemination of antimicrobial resistance and biofilm formation
Enteropathogenic bacteria use extracellular appendages, known as F-pili, to share plasmids carrying antibiotic resistance genes. Here, the authors show that F-pili are highly flexible but robust at the same time, and this is important for plasmid transfer and formation of biofilms that protect against the action of antibiotics.
- Jonasz B. Patkowski
- , Tobias Dahlberg
- & Tiago R. D. Costa
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Article
| Open AccessTackling antibiotic resistance by inducing transient and robust collateral sensitivity
In this work, the authors induce ciprofloxacin resistance in clinical isolates of Pseudomonas aeruginosa to investigate transient collateral sensitivity to tobramycin.
- Sara Hernando-Amado
- , Pablo Laborda
- & José Luis Martínez
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Article
| Open AccessThe evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis
Here using drug susceptibility profiling, genomics and evolutionary studies the authors provide strategies to exploit collateral drug responses in Mycobacterium tuberculosis to prevent the emergence of drug resistance.
- Natalie J. E. Waller
- , Chen-Yi Cheung
- & Matthew B. McNeil
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Article
| Open AccessDevelopment of the oral resistome during the first decade of life
Here, the authors provide a longitudinal genetic surveillance of the antimicrobial resistance potential of the human oral microbiome in the first decade of life, revealing a dynamic environment altered by tooth decay with the increasing potential to mobilize genes as children grow.
- Smitha Sukumar
- , Fang Wang
- & Christina J. Adler
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Article
| Open AccessMacrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance
Arastehfar et al. show that macrophage-engulfed cells of fungal pathogen Candida glabrata exhibit multidrug tolerance and increased survival in the presence of cidal antifungal drugs, forming a reservoir from which drug-resistant mutants emerge
- Amir Arastehfar
- , Farnaz Daneshnia
- & David S. Perlin
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Article
| Open AccessPopulation-level impacts of antibiotic usage on the human gut microbiome
Here, the authors study the population-level impact of antimicrobial resistance genes (ARGs). By analyzing 8972 metagenomes and 3,096 gut microbiomes from healthy individuals not taking antibiotics, they demonstrate significant correlations between both the total ARG abundance and diversity and per capita antibiotic usage rates across ten countries spanning three continents. Using a collection of 154,723 human-associated metagenome assembled genomes (MAGs) they link these ARGs to microbial taxa and horizontal gene transfer.
- Kihyun Lee
- , Sebastien Raguideau
- & Christopher Quince
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Article
| Open AccessIdentification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2
Effective antivirals are critical for combatting SARS-CoV-2 infections. Here, the authors develop two orally available small molecules, which specifically inhibit the activity of the SARS-CoV-2 main protease and potently block the infectivity and replication of various SARS-CoV-2 strains in cells and mice.
- Nobuyo Higashi-Kuwata
- , Kohei Tsuji
- & Hiroaki Mitsuya
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Article
| Open AccessAn optogenetic toolkit for light-inducible antibiotic resistance
Antibiotics are a key control mechanism for synthetic biology and microbiology. Here, using an optogenetic recombinase, the authors develop genetic constructs where antibiotic resistance levels in bacteria can be controlled using light.
- Michael B. Sheets
- , Nathan Tague
- & Mary J. Dunlop
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Article
| Open AccessAntibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria
Thermorubin is a ribosome-targeting antibiotic. Here, using fast-kinetics and cryoEM, the authors reveal that thermorubin primarily blocks ribosome-recycling by tethering the ribosomal subunits besides impeding translation elongation and termination steps.
- Narayan Prasad Parajuli
- , Andrew Emmerich
- & Suparna Sanyal