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Article
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An effective and rapidly degradable disinfectant from disinfection byproducts
Here, authors highlight ecological risks of a widely used disinfectant, chloroxylenol, and identify a more efficient and safer alternative from halo-phenolic disinfection byproducts, 2,6-dichlorobenzoquinone. They leverage seawater’s slightly alkaline nature to enhance its degradability via hydrolysis.
- Jiarui Han
- , Wanxin Li
- & Xiangru Zhang
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Article
| Open Access
β-lactamase expression induces collateral sensitivity in Escherichia coli
In this work, authors show that β-lactamase enzymes not only confer antibiotic resistance but also increase susceptibility to other antibiotics.
- Cristina Herencias
- , Laura Álvaro-Llorente
- & Jerónimo Rodríguez-Beltrán
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Article
| Open Access
Potent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid A
Polymyxins are last-resort antibiotics targeting lipid A in the gram-negative outer membrane. Here, the authors use surface plasmon resonance-based kinetics to reveal a three-state mechanism governing superstoichiometric accumulation of polymyxins.
- Kerry R. Buchholz
- , Mike Reichelt
- & John G. Quinn
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Article
| Open Access
Targeted 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
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Targeting 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 Access
Three 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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Article
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Structural 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 Access
Prey 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 Access
Colonisation 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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Article
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Plasmid-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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Article
| Open Access
Elucidation 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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Article
| Open Access
Quantitative 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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Article
| Open Access
Inhibition 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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Article
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Multi-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 Access
Targeting 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 Access
High-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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Matters Arising
| Open Access
Antibiotics and hexagonal order in the bacterial outer membrane
- Georgina Benn
- , Thomas J. Silhavy
- & Bart W. Hoogenboom
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Article
| Open Access
Profiling 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 Access
Molecular 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
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Structural 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 Access
On 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 Access
Regulation 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 Access
DprE2 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 Access
A 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 Access
Collateral 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
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Population-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
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Antibiotic 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
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The 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
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Genome-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
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Synthesis 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 Access
Suicidal 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 Access
Identifying 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
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A 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 Access
Anti-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
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Antibiotic 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 Access
Multiplexed 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 Access
A 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 Access
A 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 Access
Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies
Antibiotic tolerance, or the ability of bacteria to survive antibiotic treatment in the absence of genetic resistance, often involves a low metabolic state. Here, Zheng et al. show that tolerance does not readily evolve against antibiotics whose efficacy is only minimally affected by bacterial metabolism, and find that cycling of antibiotics with different metabolic dependencies interrupts evolution of tolerance.
- Erica J. Zheng
- , Ian W. Andrews
- & James J. Collins
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Article
| Open Access
Human serum triggers antibiotic tolerance in Staphylococcus aureus
The host environment can impact the outcomes of antimicrobial therapies through unclear mechanisms. Here, Ledger et al. show that human serum reduces the efficacy of the antibiotic daptomycin against Staphylococcus aureus by inducing specific pathways leading to changes in the composition of the bacterial membrane and cell wall.
- Elizabeth V. K. Ledger
- , Stéphane Mesnage
- & Andrew M. Edwards
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Article
| Open Access
Collateral sensitivity to pleuromutilins in vancomycin-resistant Enterococcus faecium
The acquisition of resistance to one antibiotic sometimes leads to collateral sensitivity to a second antibiotic. Here, the authors show that vancomycin resistance in Enterococcus faecium is associated with a remarkable increase in susceptibility to pleuromutilin antibiotics, such as lefamulin.
- Qian Li
- , Shang Chen
- & Jianzhong Shen
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Article
| Open Access
Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics
PoxtA confers resistance to ribosome-targeting oxazolidinone (linezolid) and chloramphenicol antibiotics. Here, Crowe-McAuliffe et al. provide structural insights into how binding of PoxtA to the ribosome indirectly promotes drug dissociation.
- Caillan Crowe-McAuliffe
- , Victoriia Murina
- & Vasili Hauryliuk
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Article
| Open Access
A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens
Polymyxins are often the last therapeutic option for multidrug-resistant (MDR) bacteria, but have suboptimal safety and efficacy. Here the authors report the discovery and development of a synthetic lipopeptide with an improved safety and efficacy against top-priority MDR Gram-negative pathogens.
- Kade D. Roberts
- , Yan Zhu
- & Jian Li
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Article
| Open Access
Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections
It remains unclear how rapid antibiotic switching affects the evolution of antibiotic resistance in individual patients. Here, Chung et al. combine short- and long-read sequencing and resistance phenotyping of 420 serial isolates of Pseudomonas aeruginosa collected from the onset of respiratory infection, and show that rare resistance mutations can increase by nearly 40-fold over 5–12 days in response to antibiotic changes, while mutations conferring resistance to antibiotics not administered diminish and even go to extinction.
- Hattie Chung
- , Christina Merakou
- & Gregory P. Priebe
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Article
| Open Access
Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial
Here, in a randomized trial of 147 infants receiving distinct antibiotic regimens for early-onset neonatal sepsis, Reyman et al. characterize the gut microbiome and resistance profiles, finding differential effects of antibiotic combinations on microbial community composition and antimicrobial resistance genes.
- Marta Reyman
- , Marlies A. van Houten
- & Debby Bogaert
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Article
| Open Access
A polytherapy based approach to combat antimicrobial resistance using cubosomes
An increasing prevalence of Gram-negative bacteria increases the interest in nanotherapies to treat antibiotic resistance. Here, the authors examine the antimicrobial activity of polymyxin-loaded cubosomes and explore a polytherapy treatment of pathogens with cubosomes in combination with polymyxin.
- Xiangfeng Lai
- , Mei-Ling Han
- & Hsin-Hui Shen
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Article
| Open Access
Serum apolipoprotein A-I potentiates the therapeutic efficacy of lysocin E against Staphylococcus aureus
Lysocin E is a lipopeptide with antibiotic activity against methicillin-resistant Staphylococcus aureus. Here, the authors show that the antimicrobial activity of lysocin E is potentiated through interactions with host serum proteins (such as apolipoprotein A-I) and bacterial membrane components.
- Hiroshi Hamamoto
- , Suresh Panthee
- & Kazuhisa Sekimizu
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Article
| Open Access
Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus
Antibiotic resistance in Staphylococcus aureus is associated with reduced neutrophil recruitment. Here, Payne et al. link formylated peptides, which act as chemoattractants for neutrophils, with the antibiotic vancomycin and show that these hybrid compounds improve clearance of S. aureus by neutrophils.
- Jennifer A. E. Payne
- , Julien Tailhades
- & Max J. Cryle
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Article
| Open Access
Design principles of collateral sensitivity-based dosing strategies
Collateral sensitivity-based antibiotic treatments may have the potential to limit the emergence of antimicrobial resistance. Here, the authors use mathematical modelling to study the effects of pathogen- and drug-specific characteristics for different treatment designs on bacterial population dynamics and resistance evolution.
- Linda B. S. Aulin
- , Apostolos Liakopoulos
- & J. G. Coen van Hasselt
Rule-based omics mining reveals antimicrobial macrocyclic peptides against drug-resistant clinical isolates