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| 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
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Article
| Open AccessThe natural pyrazolotriazine pseudoiodinine from Pseudomonas mosselii 923 inhibits plant bacterial and fungal pathogens
Natural antimicrobial metabolites produced by soil microorganisms can be used as green pesticides. Here, the authors isolated a Pseudomonas mosselii strain 923 from rice rhizosphere soils and identify the compound pyrazolotriazine pseudoiodinine inhibits the growth of plant bacterial and fungal pathogens.
- Ruihuan Yang
- , Qing Shi
- & Gongyou Chen
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Article
| Open AccessUltra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
In this study, the authors developed an ultra-long-acting injectable, biodegradable, and removable in-situ forming implant delivering cabotegravir (CAB ISFI). CAB ISFI was well tolerated and protected against multiple rectal SHIV challenges in female macaques.
- Isabella C. Young
- , Ivana Massud
- & S. Rahima Benhabbour
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Article
| Open AccessDeep mutational scanning of essential bacterial proteins can guide antibiotic development
Deep mutational scanning can be used to investigate protein function and stability. Here, Dewachter et al. use deep mutational scanning on three essential bacterial proteins to study the mutations’ effects in their original genomic context, providing insight into the proteins’ function and their potential as targets for new antibiotic development.
- Liselot Dewachter
- , Aaron N. Brooks
- & Jan Michiels
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Article
| Open AccessResolving colistin resistance and heteroresistance in Enterobacter species
Taxonomical complexity has muddled the classification of clinically relevant Enterobacter species. Authors carry out a genome-based study on clinical isolates to investigate colistin resistance and heteroresistance in Enterobacter.
- Swapnil Prakash Doijad
- , Nicolas Gisch
- & Trinad Chakraborty
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Article
| Open AccessAn ISO-certified genomics workflow for identification and surveillance of antimicrobial resistance
The implementation of genomics for identification and surveillance of antimicrobial resistance (AMR) in clinical laboratories remains challenging. Here, Sherry et al. present a bioinformatics platform for detection of AMR determinants from whole-genome sequencing data, suitable for clinical and public-health microbiology reporting.
- Norelle L. Sherry
- , Kristy A. Horan
- & Torsten Seemann
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Article
| Open AccessGenome-wide identification of genes required for alternative peptidoglycan cross-linking in Escherichia coli revealed unexpected impacts of β-lactams
β-lactam-induced bacterial killing is complex and not fully resolved. Authors carry out a genome-wide analysis, through penicillin-binding protein replacement, to identify genes essential for drug efficacy.
- Henri Voedts
- , Sean P. Kennedy
- & Jean-Emmanuel Hugonnet
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Article
| Open AccessEvolutionary rescue of resistant mutants is governed by a balance between radial expansion and selection in compact populations
Antibiotic and anti-cancer therapy are challenged by mutation-mediated treatment resistance despite many mutations being maladaptive. Here, the authors introduce a system that shows how the probability of the long-term persistence of drug-resistant mutant lineages can be increased in dense microbial populations by acquiring multiple mutations.
- Serhii Aif
- , Nico Appold
- & Jona Kayser
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Article
| Open AccessSynthesis of macrocyclic nucleoside antibacterials and their interactions with MraY
MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials.
- Takeshi Nakaya
- , Miyuki Yabe
- & Satoshi Ichikawa
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Article
| Open AccessDynamics of extended-spectrum cephalosporin resistance genes in Escherichia coli from Europe and North America
Extended-spectrum cephalosporin resistance genes in Escherichia coli have spread worldwide. Here, the authors dissect the emergence and distribution of these genes over time, and across geographic location and host species, to better understand their dynamics and mechanisms of transmission.
- Roxana Zamudio
- , Patrick Boerlin
- & Alison E. Mather
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Article
| Open AccessSuicidal chemotaxis in bacteria
Bacteria respond to nutrients and other compounds via chemotaxis, but little is known of their responses to antibiotics. By tracking cells in antibiotic gradients, the authors show that surface-attached Pseudomonas aeruginosa move towards antibiotics in what appears to be a suicidal attack strategy.
- Nuno M. Oliveira
- , James H. R. Wheeler
- & Kevin R. Foster
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Article
| Open AccessIdentifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases
Antimicrobial resistance to currently available antibiotics requires innovation of antibiotics. Here, the authors identify a critical inhibitory site in an energy-producing enzyme, which can lead to rational design of antibiotics.
- Yuya Nishida
- , Sachiko Yanagisawa
- & Yasunori Shintani
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Article
| Open AccessImpact of international travel and diarrhea on gut microbiome and resistome dynamics
Here, the authors characterize the microbiome and resistome in a longitudinal cohort of 159 international students visiting the Andean city of Cusco, Peru. They find that international travel associates with spread of antimicrobial resistance, and that travelers’ diarrhea increases a persons’ risk for acquiring antimicrobial-resistant pathogens, while a diverse, “healthy” microbiome can be protective against diarrhea.
- Manish Boolchandani
- , Kevin S. Blake
- & Gautam Dantas
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Article
| Open AccessGenomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance
Understanding the emergence, evolution, and transmission of antibiotic resistance genes (ARGs) is essential to combat antimicrobial resistance. Here, Munk et al. analyse ARGs in hundreds of sewage samples from 101 countries and describe regional patterns, diverse genetic environments of common ARGs, and ARG-specific transmission patterns.
- Patrick Munk
- , Christian Brinch
- & Frank M. Aarestrup
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Article
| Open AccessA Shigella sonnei clone with extensive drug resistance associated with waterborne outbreaks in China
Shigella sonnei is a major contributor to the global burden of dysenteric diarrhoea in developed countries. In this work, authors report a S. sonnei clone which has caused numerous waterborne shigellosis outbreaks in China from 2015 to 2020.
- Shaofu Qiu
- , Kangkang Liu
- & Hongbin Song
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Article
| Open AccessHost-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter
There is increasing evidence for metabolic processes mediating antimicrobial resistance. Here, the authors present a mechanism of sulfamethoxazole resistance in Group A Streptococcus that is dependent on acquiring end products of the host folate biosynthesis pathway.
- M. Kalindu D. Rodrigo
- , Aarti Saiganesh
- & Timothy C. Barnett
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Article
| Open AccessGut to lung translocation and antibiotic mediated selection shape the dynamics of Pseudomonas aeruginosa in an ICU patient
In this paper the authors show that the pathogenic bacterium Pseudomonas aeruginosa migrates between the gut and lungs of an ICU patient, and that differential evolutionary responses to antibiotic treatment occur in these organs.
- Rachel M. Wheatley
- , Julio Diaz Caballero
- & R. Craig MacLean
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| Open AccessAnti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
The development of selective ClpP activators targeting only the MRSA isolates without interfering with the human variant is currently challenging. Here, the authors report on the structure-based design of enantiomers of ZG197 and identify the discriminator factor between the proteins.
- Bingyan Wei
- , Tao Zhang
- & Cai-Guang Yang
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Article
| Open AccessAn active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M β-lactamase drug-resistance enzymes
β-lactamases are a source of antibiotic resistance. Here, the authors show that an active site loop in β-lactamase toggles between conformations that control antibiotic hydrolysis and inhibitor susceptibility, highlighting the role of active site conformations in enzyme activity and inhibition.
- Shuo Lu
- , Liya Hu
- & Timothy Palzkill
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Article
| Open AccessCellular glycan modification by B3GAT1 broadly restricts influenza virus infection
Identification of host antiviral restriction factors could provide targets for antiviral therapy. Here, using a genome-wide CRISPR screen, the authors identify the glycosyltransferase B3GAT1 as a host protein which, when ectopically overexpressed, restricts influenza virus infection in vitro and in mice, as well as other viruses relying on sialic acid for entry.
- Joseph D. Trimarco
- , Sarah L. Nelson
- & Nicholas S. Heaton
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Comment
| Open AccessSeeing the unseen: High-resolution AFM imaging captures antibiotic action in bacterial membranes
Advances in atomic force microscopy (AFM) techniques and methodologies for microbiology contribute to our understanding of the microbial cell surface. Recent studies show that AFM imaging of cells and membranes at (near) molecular resolution allows detailed visualization of membranes interacting with drugs.
- Telmo O. Paiva
- , Albertus Viljoen
- & Yves F. Dufrêne
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Article
| Open AccessAntibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane
Manioglu et al use high-resolution atomic force microscopy to resolve how polymyxins interact with the bacterial membrane. Polymyxins arrange the bacterial lipids into regular hexagonal structures that stiffen the membrane and lead to rupture.
- Selen Manioglu
- , Seyed Majed Modaresi
- & Sebastian Hiller
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Article
| Open AccessRapid antibiotic susceptibility testing and species identification for mixed samples
Rapid antibiotic susceptibility testing (AST) is needed. Here the authors report a method for phenotypic AST at the single cell level, using a microfluidic chip that allows for subsequent genotyping with in situ FISH; they apply this to a mixed sample of 7 species and 4 antibiotics.
- Vinodh Kandavalli
- , Praneeth Karempudi
- & Johan Elf
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Article
| Open AccessEffect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial
Many survivors of COVID-19 experience persistent symptoms, continuing beyond three months from the onset of infection. In this study, authors investigate the effect of remdesivir on recovery and long-COVID-19 symptoms, as well as quality of life and other symptom outcomes, in the 1-year follow-up of a randomised trial.
- Olli P. O. Nevalainen
- , Saana Horstia
- & Kari A. O. Tikkinen
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Article
| Open AccessEnvironmental complexity is more important than mutation in driving the evolution of latent novel traits in E. coli
Novel traits without immediate fitness benefit evolve frequently but we don’t know whether mutation or environment-driven selection drives this evolution. Here, using experimental evolution of E. coli populations, the authors demonstrate the importance of selection in the evolution of latent novel traits.
- Shraddha Karve
- & Andreas Wagner
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Article
| Open AccessBacteriophage-antibiotic combination therapy against extensively drug-resistant Pseudomonas aeruginosa infection to allow liver transplantation in a toddler
In this study, authors use combinatory bacteriophage-antibiotic therapy, as treatment for extensively drug-resistant Pseudomonas aeruginosa infection in a toddler post liver transplantation. They report on the clinical and microbiological improvement, and present their investigation on how bacterial phage resistance did not result in therapeutic failure.
- Brieuc Van Nieuwenhuyse
- , Dimitri Van der Linden
- & Jean-Paul Pirnay
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Article
| Open AccessHigh-throughput small molecule screen identifies inhibitors of microsporidia invasion and proliferation in C. elegans
Microsporidia are fungal-related intracellular parasites that infect animals and humans. Here, Murareanu et al. develop a high-throughput screening method using the nematode C. elegans as a host, and identify several compounds that inhibit microsporidia infection through different mechanisms.
- Brandon M. Murareanu
- , Noelle V. Antao
- & Aaron W. Reinke
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Review Article
| Open AccessThe importance of antimicrobial resistance in medical mycology
The impact of fungal infections on human health has been exacerbated by the rise of antifungal drug resistance. In this Review, the authors outline the problem of antifungal resistance and suggest how this growing threat might be mitigated.
- Neil A. R. Gow
- , Carolyn Johnson
- & Keegan Edgar
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Article
| Open AccessMultiplexed mobilization and expression of biosynthetic gene clusters
Efficient mobilization and expression of biosynthetic gene clusters (BGCs) into heterologous hosts is needed for microbial natural products discovery. Here, the authors improve the CONKAT-seq strategy by simultaneously capturing the BCGs into a single large insert library and demonstrate its ability to discover natural products with new structures and potent antibacterial activity.
- Vincent Libis
- , Logan W. MacIntyre
- & Sean F. Brady
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Article
| Open AccessTackling recalcitrant Pseudomonas aeruginosa infections in critical illness via anti-virulence monotherapy
Pseudomonas aeruginosa infections are increasingly difficult to treat due to the development of antimicrobial resistance. Here, the authors describe the synthesis, characterisation and efficacy of a quorum sensing inhibitor.
- Vijay K. Singh
- , Marianna Almpani
- & Laurence G. Rahme
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Article
| Open AccessCopper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
The genomes of filamentous fungi, such as Aspergillus, include many biosynthetic gene clusters of unknown function. Here, the authors show that copper starvation induces expression of an enzyme that generates a valine-derived isocyanide participating in two different pathways, for biosynthesis of acylated sugar alcohols and modified ergot alkaloids.
- Tae Hyung Won
- , Jin Woo Bok
- & Frank C. Schroeder
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Article
| Open AccessAdenosine triphosphate-activated prodrug system for on-demand bacterial inactivation and wound disinfection
Prodrugs are increasingly promising in tackling bacterial resistance and efficacy of treatment. Here, the authors encapsulated horseradish peroxidase and zeolitic imidazolate framework-8 loaded with indole-3-acetic acid in polyacrylamide hydrogel microspheres for ATP-activated wound disinfection.
- Yuhao Weng
- , Huihong Chen
- & Hongliang Tan
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Article
| Open AccessA long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis
Non-adherence to anti-tubercular therapy Mycobacterium tuberculosis infection can lead to treatment failure and even the development of drug resistance. In this work, the authors develop a long-acting delivery system of the anti-tuberculosis drug rifabutin and assess translational potential in vivo.
- Manse Kim
- , Claire E. Johnson
- & Martina Kovarova
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Article
| Open AccessDistinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis
This manuscript elucidates new mechanisms of mutagenesis in mycobacteria by implicating two translesion DNA polymerases in genome diversification, including creating the mutations that underlie all antibiotic resistance in these global pathogens.
- Pierre Dupuy
- , Shreya Ghosh
- & Michael S. Glickman
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Article
| Open AccessSARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model
Molnupiravir was the first orally available SARS-CoV-2 antiviral approved for outpatient use against SARS-CoV-2, but its efficacy against variants of concern, especially delta, was questioned. Here the authors evaluate molnupiravir against variant of concern in numerous models, including human airway epithelium organoids, ferrets and Roborovski dwarf hamsters.
- Carolin M. Lieber
- , Robert M. Cox
- & Richard K. Plemper
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Article
| Open AccessA unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile
Antibiotics of the β-lactam class inhibit bacterial cell wall synthesis by targeting penicillin-binding proteins (PBPs). Here, Sacco et al. study the four PBPs present in the pathogen C. difficile, revealing unique structural features and shedding light on the mechanisms underlying β-lactam resistance in this organism.
- Michael D. Sacco
- , Shaohui Wang
- & Yu Chen
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Article
| Open AccessThe Cryo-EM structures of two amphibian antimicrobial cross-β amyloid fibrils
In this work the authors provide high-resolution structural support for the amyloid-antimicrobial link via functional amyloids displaying propeller-like and kinked cross-β fibrils.
- Robert Bücker
- , Carolin Seuring
- & Meytal Landau
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Article
| Open AccessDevelopment of a novel core genome MLST scheme for tracing multidrug resistant Staphylococcus capitis
Staphylococcus capitis is a common causative agent of bloodstream infections in neonatal intensive care units, with multidrug resistant isolates complicating treatment. Authors aimed to establish a core genome multilocus sequence typing (cgMLST) scheme to document the transmission and dissemination of multidrug-resistant S. capitis isolates.
- Zhengan Wang
- , Chao Gu
- & Yunsong Yu
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Article
| Open AccessPotentiating hypoxic microenvironment for antibiotic activation by photodynamic therapy to combat bacterial biofilm infections
Bacteria in biofilms present unique metabolic conditions that limit the traditional antibiotic treatment. Here, the authors show a photodynamic therapy-activated chemotherapy potentiating the hypoxia of biofilms of methicillin-resistant Staphylococcus aureus, by developing hyaluronic acid nanoparticles functionalized with chlorin e6 and metronidazole.
- Weijun Xiu
- , Ling Wan
- & Lianhui Wang
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Article
| Open AccessA convolutional neural network highlights mutations relevant to antimicrobial resistance in Mycobacterium tuberculosis
Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution to multi-drug resistance diagnosis. Here, the authors present two deep convolutional neural networks that predict the antibiotic resistance phenotypes of M. tuberculosis isolates.
- Anna G. Green
- , Chang Ho Yoon
- & Maha Farhat
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Article
| Open AccessComparative genomics of Acinetobacter baumannii and therapeutic bacteriophages from a patient undergoing phage therapy
A patient with a multidrug-resistant bacterial infection was successfully treated in 2016 using phage therapy. Here, the authors sequence the genomes of the therapeutic phages and three bacterial strains isolated before and during treatment, and show that the same mutations conferring phage resistance are found in in vitro-generated mutants and in phage-insensitive strains isolated from the patient.
- Mei Liu
- , Adriana Hernandez-Morales
- & Jason J. Gill
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Article
| Open AccessTargeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation
There is an urgent need for novel strategies to combat life-threatening fungal infections. Here, Revie et al. identify a compound that induces alterations in fungal membranes, synergizes with azole antifungals against the pathogen Candida albicans, and inhibits virulence traits and biofilm formation in animal models of infection.
- Nicole M. Revie
- , Kali R. Iyer
- & Leah E. Cowen
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Article
| Open AccessRNase III-CLASH of multi-drug resistant Staphylococcus aureus reveals a regulatory mRNA 3′UTR required for intermediate vancomycin resistance
Regulatory small RNA (sRNA) interact with mRNAs to regulate their stability, transcription, and translation via diverse mechanisms. Here, Mediati et al. apply RNase III-CLASH to multidrug-resistant Staphylococcus aureus to characterise the network of RNA–RNA interactions associated with RNase III and identify a regulatory mRNA 3′UTR, named vigR-3′UTR, involved in the regulation of genes relevant for vancomycin sensitivity.
- Daniel G. Mediati
- , Julia L. Wong
- & Jai J. Tree
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Article
| Open AccessEvolutionary action of mutations reveals antimicrobial resistance genes in Escherichia coli
The emergence of antibiotic resistance, even against last-line antibiotics such as colistin, is a serious public health threat. To guide treatment and drug development strategies, Marciano et al. apply evolutionary action (EA) analysis to identify driver mutations in a noisy mutational background in experimental evolution experiments and inform about de novo colistin resistance drivers.
- David C. Marciano
- , Chen Wang
- & Olivier Lichtarge
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Article
| Open AccessA genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance
A lack of understanding in the development and emergence of antimicrobial resistance presents as a problem for accurate infection diagnosis and treatment. Here, authors utilize Streptococcus pneumoniae and build a genome-wide atlas to understand the genes and interactions that contribute to altered drug susceptibility.
- Dmitry Leshchiner
- , Federico Rosconi
- & Tim van Opijnen
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Article
| Open AccessWhole genome sequencing reveals hidden transmission of carbapenemase-producing Enterobacterales
Carbapenemase-producing Enterobacterales cause healthcare-associated infections but modes of transmission are not well understood. Here, the authors find evidence of transmission without direct patient contact, indicating presence of undetected environmental reservoirs, whilst half of the transmission events are likely due to plasmid-mediated transmission.
- Kalisvar Marimuthu
- , Indumathi Venkatachalam
- & Oon Tek Ng
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Article
| Open AccessGenomic dissection of Klebsiella pneumoniae infections in hospital patients reveals insights into an opportunistic pathogen
Klebsiella pneumoniae is an opportunistic pathogen of increasing public health concern due to the prevalence of antimicrobial resistance. Here, the authors provide insight into the resistance profiles, bacterial genome features and virulence genes, in a year-long prospective study of K. pneumoniae clinical isolates.
- Claire L. Gorrie
- , Mirjana Mirčeta
- & Kathryn E. Holt