Featured
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| Open AccessDynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy
Tuberculosis is a major global health threat. Here, the authors develop a single-cell drug discovery approach and identify a compound that tunes bacterial phenotypic variation. This enhances the activity of anti-tubercular drugs against the pathogen.
- Maxime Mistretta
- , Mena Cimino
- & Giulia Manina
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| Open AccessTargeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy
Efforts to apply targeted protein degradation for antibiotic development are limited by our understanding of prokaryotic protein degradation. Here, the authors establish a chemical-genetic platform and predictive model to determine the degradation potential of essential mycobacterial proteins.
- Harim I. Won
- , Samuel Zinga
- & Junhao Zhu
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Article
| Open AccessTargeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes
Aspergillomarasmine A (AMA) chelates metal ions such as Zn2+ and Ni2+, which are essential for the activity of enzymes that are important for virulence of several pathogens. Here, Sychantha et al. show that AMA inhibits bacterial Ni2+ uptake and Ni-dependent enzymes, and reduces bacterial virulence in an animal infection model.
- David Sychantha
- , Xuefei Chen
- & Gerard D. Wright
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Article
| Open AccessMultimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88
Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial protein biosynthesis. Here, the authors show that the honey-bee derived PrAMPs Api137 and Api88 inhibit bacterial ribosomes through multiple mechanisms, promising for drug development.
- Simon M. Lauer
- , Maren Reepmeyer
- & Ralf Hoffmann
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Article
| Open AccessThree concurrent mechanisms generate gene copy number variation and transient antibiotic heteroresistance
Bacterial heteroresistance is a medically relevant phenotype where small antibiotic-resistant subpopulations coexist within predominantly susceptible bacterial populations. Here, Nicoloff et al. describe how three different mechanisms that increase the copy number of resistance genes can lead to unstable and transient heteroresistance.
- Hervé Nicoloff
- , Karin Hjort
- & Helen Wang
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| Open AccessAn oxylipin signal confers protection against antifungal echinocandins in pathogenic aspergilli
Echinocandins are antifungal drugs that inhibit hyphal growth and induce lysis of hyphal tip compartments in pathogenic Aspergillus species. Here, Calise et al. show that echinocandins induce production of a fungal oxylipin signal, thus triggering hyphal growth changes that reduce hyphal tip lysis and confer echinocandin tolerance.
- Dante G. Calise
- , Sung Chul Park
- & Nancy P. Keller
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Article
| Open AccessEvolution of triclosan resistance modulates bacterial permissiveness to multidrug resistance plasmids and phages
In this work, Yang et al. provide evidence of triclosan exposure resulting in increased evolvability of K. pneumoniae in experimental evolution studies. They utilize sequencing and transcriptomics to explore the chromosomally and horizontally acquired antimicrobial resistance mechanisms.
- Qiu E. Yang
- , Xiaodan Ma
- & Timothy R. Walsh
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| Open AccessA secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1
Triazole antifungals are widely used and exert their action by inhibiting ergosterol biosynthesis. Here, Rybak et al show that these drugs both inhibit ergosterol biosynthesis and induce accumulation of pathway intermediates that directly induce inhibition of sterol synthesis.
- Jeffrey M. Rybak
- , Jinhong Xie
- & Jarrod R. Fortwendel
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Article
| Open AccessHIV transmission dynamics and population-wide drug resistance in rural South Africa
There is limited data on drug resistance in South African communities strongly affected by HIV. In this study, the authors observed low levels of resistance to newer drugs but widespread resistance to older HIV medications in a South African community. Resistance to rilpivirine was detected even in untreated individuals.
- Steven A. Kemp
- , Kimia Kamelian
- & Ravindra K. Gupta
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Article
| Open AccessStructural insights into the transporting and catalyzing mechanism of DltB in LTA D-alanylation
Here, the authors structurally and functionally characterise DltB, a member of the Membrane-Bound O-AcylTransferase (MBOAT) superfamily responsible for D-alanine incorporation in the cell wall of gram-positive bacteria.
- Pingfeng Zhang
- & Zheng Liu
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Article
| Open AccessSynergistic effect of two human-like monoclonal antibodies confers protection against orthopoxvirus infection
In this study, the authors show that a single dose of a combination of two human-like monoclonal antibodies protect mice in therapeutic treatment against challenges with ectromelia virus and monkeypox virus. Combination treatment provided more effective viral clearance than single antibody treatment.
- Hadas Tamir
- , Tal Noy-Porat
- & Tomer Israely
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Article
| Open AccessPrey killing without invasion by Bdellovibrio bacteriovorus defective for a MIDAS-family adhesin
The bacterium Bdellovibrio bacteriovorus is a predator of other bacteria, invading the prey’s periplasm and forming a rounded killed cell where it replicates. Here, Tyson et al. identify a B. bacteriovorus protein that is important for successful invasion of prey, and show that prey killing can occur without invasion.
- Jess Tyson
- , Paul Radford
- & R. Elizabeth Sockett
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Article
| Open AccessPhage-specific immunity impairs efficacy of bacteriophage targeting Vancomycin Resistant Enterococcus in a murine model
Bacteriophage can be used to target bacterial infection and used as a therapeutic approach for antibiotic resistant bacteria. Here the authors show that the use of bacteriophage to target antibiotic resistant bacteria in a mouse model of infection can induce phage specific immune responses and may impair their therapeutic efficacy.
- Julia D. Berkson
- , Claire E. Wate
- & Paul E. Carlson Jr.
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| Open AccessColonisation of hospital surfaces from low- and middle-income countries by extended spectrum β-lactamase- and carbapenemase-producing bacteria
In hospitals, surfaces present as a reservoir for bacteria pathogens, potentially leading to nosocomial infections. In this work, authors aim to profile extended-spectrum β lactamase- and carbapenemase-carrying bacterial species colonising neonatal hospital wards and causing neonatal sepsis.
- Maria Nieto-Rosado
- , Kirsty Sands
- & Timothy R. Walsh
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| Open AccessPlasmid-mediated phenotypic noise leads to transient antibiotic resistance in bacteria
In this work, authors combine computational models with single-cell and population-level data showing the variability in plasmid copy number within bacterial populations leads to phenotypic diversity. They reveal how multicopy plasmids contribute to bacterial transient antibiotic resistance.
- J. Carlos R. Hernandez-Beltran
- , Jerónimo Rodríguez-Beltrán
- & Rafael Peña-Miller
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| Open AccessMutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance
Mutations in mexZ, encoding a negative regulator of efflux pump genes, are frequently acquired by Pseudomonas aeruginosa during early lung infection, but do not confer high antibiotic resistance as measured in lab tests. Here, Laborda et al. show that mexZ mutations affect quorum sensing pathways, thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within tissues.
- Pablo Laborda
- , Signe Lolle
- & Helle Krogh Johansen
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| Open AccessBacteria can compensate the fitness costs of amplified resistance genes via a bypass mechanism
Antibiotic heteroresistance, in which a susceptible bacterial population includes a small resistant subpopulation, can arise by tandem amplification of resistance genes, which often carry fitness costs. Here, Pal and Andersson show that these fitness costs can be ameliorated by the acquisition of compensatory mutations and a reduction in copy number of the resistance genes.
- Ankita Pal
- & Dan I. Andersson
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| Open AccessCharacterisation of colistin resistance in Gram-negative microbiota of pregnant women and neonates in Nigeria
Here, the authors report the results of a BARNARDS sub-study identifying a 1% mobile colistin resistance gene (mcr) carriage rate in around 5000 rectal swabs from mothers and neonates across Nigeria, of which 90% were mcr-10 (mostly Enterobacter spp.) and 10% were mcr-1 and mcr9.
- E. A. R. Portal
- , K. Sands
- & O. B. Spiller
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| Open AccessDeep learning model for personalized prediction of positive MRSA culture using time-series electronic health records
Identification of patients at high risk of methicillin-resistant Staphylococcus aureus (MRSA) infection could improve treatment outcomes by optimising antimicrobial therapy. Here the authors develop a deep learning model that uses electronic health record data from the United States to predict MRSA culture positivity.
- Masayuki Nigo
- , Laila Rasmy
- & Degui Zhi
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| Open AccessHomo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria
Antimicrobial resistance is a global health threat and the development of alternative strategies to overcome it is of high interest. Here, the authors report proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery, and apply them for targeting a range of mycobacterial strains, including antibiotic-resistant ones.
- Lukas Junk
- , Volker M. Schmiedel
- & Guido Boehmelt
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| Open AccessDeaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance
Here, the authors show that two mutations in the Plasmodium de-ubiquitinase UBP1 alter the ubiquitination level, membrane localization, and ligand transport direction of multidrug resistance transporter 1 (MDR1), leading to multiple drug resistances.
- Ruixue Xu
- , Lirong Lin
- & Jian Li
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| Open AccessNucleocapsid protein-specific monoclonal antibodies protect mice against Crimean-Congo hemorrhagic fever virus
There are limited treatment options for infection with Crimean-Congo hemorrhagic fever virus in humans. Here, the authors show that a monoclonal antibody targeting the highly conserved viral nucleocapsid protein provides protective effects in a mouse model of infection.
- Aura R. Garrison
- , Vanessa Moresco
- & Joseph W. Golden
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| Open AccessRandomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients
In this clinical trial, the authors show that a 5-day molnupiravir treatment reduces SARS-CoV-2 viral load in at-risk outpatients by day 5 but mostly fails to clear virus, leads to lower spike antibody response by day 14 and higher virus mutation rates.
- Joseph F. Standing
- , Laura Buggiotti
- & Francis Yongblah
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| Open AccessThe plasmidome associated with Gram-negative bloodstream infections: A large-scale observational study using complete plasmid assemblies
Plasmids carry antimicrobial resistance genes and contribute to the rapid dissemination of resistance. Here, the authors sequence 1,880 complete plasmids from 738 isolates from bloodstream infections, shedding light on the links between plasmid types, bacterial hosts and antimicrobial resistance.
- Samuel Lipworth
- , William Matlock
- & Nicole Stoesser
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| Open AccessExploiting lung adaptation and phage steering to clear pan-resistant Pseudomonas aeruginosa infections in vivo
In this work, authors utilise a pan-resistant Pseudomonas aeruginosa in vivo infection model to demonstrate antibiotic re-sensitisation with bacteriophage therapy.
- Eleri A. Ashworth
- , Rosanna C. T. Wright
- & Joanne L. Fothergill
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Article
| Open AccessDuplicated antibiotic resistance genes reveal ongoing selection and horizontal gene transfer in bacteria
Mobile genetic elements can promote the duplication of antibiotic resistance genes which may in turn accelerate the evolution of resistance to new drugs. Here, the authors show that duplicated antibiotic resistance genes are enriched in bacterial isolates from environments associated with rampant antibiotic use.
- Rohan Maddamsetti
- , Yi Yao
- & Lingchong You
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Article
| Open AccessTherapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets
Measles virus infection causes immunosuppression and it’s unclear whether this can be prevented by antivirals. Here, using a canine distemper virus ferret model, the authors show that measles-like immune amnesia and lethal exacerbated respiratory disease after consecutive respiratory virus infections can be mitigated by oral antiviral therapy initiated at the onset of primary clinical signs.
- Robert M. Cox
- , Josef D. Wolf
- & Richard K. Plemper
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| Open AccessHormonal steroids induce multidrug resistance and stress response genes in Neisseria gonorrhoeae by binding to MtrR
Transcriptional regulator MtrR inhibits the expression of the multidrug efflux pump operon mtrCDE in Neisseria gonorrhoeae. Here, Hooks et al. show that hormonal steroids bind to MtrR and decrease its affinity for cognate promoters, thus leading to increased mtrCDE expression and enhanced antimicrobial resistance.
- Grace M. Hooks
- , Julio C. Ayala
- & Richard G. Brennan
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| Open AccessIdentification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants
Most recent SARS-CoV-2 variants showed exceptional immune evasion properties. Here, the authors identify a highly conserved epitope within the RBD targeted by a broad spectrum neutralizing antibody BA7535 that shows therapeutic antiviral potency in mouse studies.
- Yanqun Wang
- , An Yan
- & Jincun Zhao
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| Open AccessElucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins
Mycoplanecins show promising activity against tuberculosis. Here, the authors identify and study mycoplanecins’ biosynthesis, antibacterial effects, and binding mechanism to DnaN, suggesting potential for fighting multidrug-resistant tuberculosis.
- Chengzhang Fu
- , Yunkun Liu
- & Rolf Müller
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| Open AccessGlobal surveillance of antimicrobial resistance in food animals using priority drugs maps
Monitoring antimicrobial resistance in food animals is challenging due to limited surveillance systems. Here, the authors combine data from point prevalence surveys in lower- and middle-income settings to map resistance to seven antimicrobials and predict which are likely to exceed key resistance thresholds.
- Cheng Zhao
- , Yu Wang
- & Thomas P. Van Boeckel
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| Open AccessRapid and visual identification of β-lactamase subtypes for precision antibiotic therapy
The rapid identification of drug-resistant bacteria is vital for effective treatment and to avoid antibiotic misuse. Here authors report a paper-based sensor which utilises chromogenic carbapenem and cephalosporin substrates for the identification and discrimination of β-lactamase subtypes.
- Wenshuai Li
- , Jingqi Li
- & Dingbin Liu
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| Open AccessHost- plasmid network structure in wastewater is linked to antimicrobial resistance genes
Authors apply theory and microbial ecology modelling to a wastewater sample, and show that antimicrobial resistance carrying plasmids interact with a higher number and more diverse range of bacteria than plasmids that do not carry resistance genes.
- Alice Risely
- , Arthur Newbury
- & Dirk Sanders
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| Open AccessQuantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach
Molecular diagnostics for tuberculosis have focused on predicting drug susceptibilities in a binary manner (i.e., strains are either susceptible or resistant). Here, CRyPTIC Consortium researchers use whole genome sequencing and a quantitative assay to identify associations between genomic mutations and minimum inhibitory concentrations in over 15,000 Mycobacterium tuberculosis clinical isolates.
- Ivan Barilar
- , Simone Battaglia
- & Baoli Zhu
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| Open AccessConvergence of resistance and evolutionary responses in Escherichia coli and Salmonella enterica co-inhabiting chicken farms in China
Bacteria in the same environment can share genetic material but the extent to which this influences development of antimicrobial resistance is unclear. Here, the authors investigate the evidence for co-evolution of antimicrobial resistance in bacteria found coexisting in animals and the environment in chicken farms and slaughterhouses in China.
- Michelle Baker
- , Xibin Zhang
- & Tania Dottorini
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| Open AccessA stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential
The ongoing emergence of highly pathogenic viruses that evade immune-based therapies or lack interventions mandates new approaches, especially for on-demand prophylaxis. Here the authors provide a stapled lipopeptide platform for the rapid development of viral fusion inhibitors to combat outbreaks.
- Gregory H. Bird
- , J. J. Patten
- & Loren D. Walensky
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| Open AccessThe antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients
Here, by performing tracheal aspirate RNA sequencing of critically ill patients, the authors find that older age associates with a greater number of detectably expressed antimicrobial resistance genes in the lower respiratory tract microbiome.
- Victoria T. Chu
- , Alexandra Tsitsiklis
- & Charles R. Langelier
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| Open AccessWithin-host genetic diversity of extended-spectrum beta-lactamase-producing Enterobacterales in long-term colonized patients
The diversity of ESBL-producing Klebsiella pneumoniae species complex and ESBL-Escherichia coli within patients is low and colonization with the same strain may persist for long periods. Authors utilise clinical and microbiological data from electronic health records to investigate genetic diversity of colonizing and infecting strains.
- Lisandra Aguilar-Bultet
- , Ana B. García-Martín
- & Sarah Tschudin-Sutter
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Article
| Open AccessInhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide
The mode of action of the tuberculosis antibiotic pyrazinamide is poorly understood. Here, Krug et al show that pyrazinamide inhibits the immune regulator PARP1 and demonstrate PARP1 inhibition as a host-directed therapy.
- Stefanie Krug
- , Manish Gupta
- & William R. Bishai
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| Open AccessANCA: artificial nucleic acid circuit with argonaute protein for one-step isothermal detection of antibiotic-resistant bacteria
Antibiotic-resistant bacteria pose a growing threat to global health. Here, the authors present an artificial nucleic acid circuit with argonaute protein (ANCA) for one-step, amplification-free, and isothermal detection of carbapenemase-producing Klebsiella pneumoniae.
- Hyowon Jang
- , Jayeon Song
- & Taejoon Kang
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| Open AccessNational genomic surveillance integrating standardized quantitative susceptibility testing clarifies antimicrobial resistance in Enterobacterales
Kayama et al. present a blueprint for a national genomic surveillance study that conducts genome sequencing of thousands of strains, integrates standardized quantitative antimicrobial susceptibility testing, and characterizes antimicrobial resistance determinants.
- Shizuo Kayama
- , Koji Yahara
- & Motoyuki Sugai
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Article
| Open AccessKlebsiella pneumoniae clinical isolates with features of both multidrug-resistance and hypervirulence have unexpectedly low virulence
Convergent strains, those containing characteristics of both multidrug-resistant & hypervirulent Klebsiella pneumoniae, are a global threat to public health. In this work, authors analyse convergent isolates from the United States and reveal unexpectantly low virulence.
- Travis J. Kochan
- , Sophia H. Nozick
- & Alan R. Hauser
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| Open AccessMulti-omics analysis of hospital-acquired diarrhoeal patients reveals biomarkers of enterococcal proliferation and Clostridioides difficile infection
Antibiotics can cause hospital-acquired diarrhoea, resulting in gut microbiota and metabolome changes. Here, the authors study the faecal microbiota and metabolome of 169 patients, offering insights into these changes, and identified biomarkers for diagnostics.
- Marijana Bosnjak
- , Avinash V. Karpe
- & Dena Lyras
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Article
| Open AccessGlobal pathogenomic analysis identifies known and candidate genetic antimicrobial resistance determinants in twelve species
A global analysis of antimicrobial resistance (AMR) across 27,155 genomes and 69 drugs reveals patterns in AMR gene transfer between species and identifies 142 AMR gene candidates, two of which were tested and confirmed as contributing to AMR.
- Jason C. Hyun
- , Jonathan M. Monk
- & Bernhard O. Palsson
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| Open AccessClinically relevant antibiotic resistance genes are linked to a limited set of taxa within gut microbiome worldwide
Antimicrobial resistance genes (ARGs) in commensal gut bacteria may act as a reservoir for acquisition by pathogens. Here, the authors assess the distribution and transfer potential of ARGs in gut microbiomes and find that clinically important ARGs are taxonomically restricted despite being associated with mobile plasmids
- Peter J. Diebold
- , Matthew W. Rhee
- & Ilana L. Brito
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| Open AccessCell-free biosynthesis combined with deep learning accelerates de novo-development of antimicrobial peptides
Deep learning holds a great promise for the discovery and design of bioactive peptides, but experimental approaches to validate candidates in high throughput and at low cost are needed. Here, the authors combine deep learning and cell free biosynthesis for antimicrobial peptide (AMP) development and identify 30 functional AMPs, of which six with broad-spectrum activity against drug-resistant pathogens.
- Amir Pandi
- , David Adam
- & Tobias J. Erb
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| Open AccessTargeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides
In this work the authors describe antimicrobial peptides (AMPs)-driven phase transitions of intracellular nucleic acids, whereby AMPs induce compaction and phase separation of nucleic acids, resulting in their sequestration and eventual cell death.
- Tomas Sneideris
- , Nadia A. Erkamp
- & Tuomas P. J. Knowles
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Article
| Open AccessStaphylococcus aureus sacculus mediates activities of M23 hydrolases
In this work, the authors provide structural insights into the interaction of two evolutionarily related peptidoglycan hydrolases, lysostaphin and LytM with S. aureus sacculus, and propose a model in which PG crosslinking affects their activity differently.
- Alicja Razew
- , Cedric Laguri
- & Jean-Pierre Simorre
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| Open AccessAssessing the global risk of typhoid outbreaks caused by extensively drug resistant Salmonella Typhi
Extensively drug resistant (XDR) typhoid fever is an emerging global health threat. This study compares data on air travel patterns and typhoid incidence to identify countries at high risk for XDR typhoid outbreaks.
- Joseph Walker
- , Chrispin Chaguza
- & Virginia E. Pitzer