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An Interdisciplinary Research Centre at the University of Cambridge

Evaluating traces of Hebbian plasticity in the <em>Drosophila</em> antennal lobe

Mon, 04/12/2023 - 11:00

Proc Natl Acad Sci U S A. 2023 Dec 12;120(50):e2315790120. doi: 10.1073/pnas.2315790120. Epub 2023 Dec 4.


PMID:38048452 | DOI:10.1073/pnas.2315790120

Effects of the G-quadruplex-binding drugs quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum

Sat, 02/12/2023 - 11:00

Int J Parasitol Drugs Drug Resist. 2023 Nov 24;23:106-119. doi: 10.1016/j.ijpddr.2023.11.007. Online ahead of print.


Plasmodium falciparum is the deadliest causative agent of human malaria. This parasite has historically developed resistance to most drugs, including the current frontline treatments, so new therapeutic targets are needed. Our previous work on guanine quadruplexes (G4s) in the parasite's DNA and RNA has highlighted their influence on parasite biology, and revealed G4 stabilising compounds as promising candidates for repositioning. In particular, quarfloxin, a former anticancer agent, kills blood-stage parasites at all developmental stages, with fast rates of kill and nanomolar potency. Here we explored the molecular mechanism of quarfloxin and its related derivative CX-5461. In vitro, both compounds bound to P. falciparum-encoded G4 sequences. In cellulo, quarfloxin was more potent than CX-5461, and could prevent establishment of blood-stage malaria in vivo in a murine model. CX-5461 showed clear DNA damaging activity, as reported in human cells, while quarfloxin caused weaker signatures of DNA damage. Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in both Plasmodium parasites and mammalian cells, whereas the complete antimalarial mode of action of quarfloxin may be parasite-specific and remains somewhat elusive.

PMID:38041930 | DOI:10.1016/j.ijpddr.2023.11.007

Proinflammatory cytokines driving cardiotoxicity in Covid-19

Sat, 02/12/2023 - 11:00

Cardiovasc Res. 2023 Dec 2:cvad174. doi: 10.1093/cvr/cvad174. Online ahead of print.


AIMS: Cardiac involvement is common in patients hospitalised with COVID-19 and correlates with an adverse disease trajectory. While cardiac injury has been largely attributed to direct viral cytotoxicity, serum-induced cardiotoxicity secondary to serological hyperinflammation constitutes a potentially amenable mechanism that remains largely unexplored.

METHODS AND RESULTS: To investigate serological drivers of cardiotoxicity in COVID-19 we have established a robust bioassay that assessed the effects of serum from COVID-19 confirmed patients on human embryonic stem cell (hESC)-derived cardiomyocytes. We demonstrate that serum from COVID-19 positive patients significantly reduced cardiomyocyte viability independent of viral transduction, an effect that was also seen in acute respiratory distress syndrome (ARDS). Serum from patients with greater disease severity led to worse cardiomyocyte viability and this significantly correlated with levels of key inflammatory cytokines, including IL-6, TNF-α, IL1-β, IL-10, CRP and neutrophil to lymphocyte ratio with a specific reduction of CD4+ and CD8+ cells. Combinatorial blockade of IL-6 and TNF-α partly rescued the phenotype and preserved cardiomyocyte viability and function. Bulk RNA sequencing of serum-treated cardiomyocytes elucidated specific pathways involved in the COVID-19 response impacting cardiomyocyte viability, structure and function. The observed effects of serum-induced cytotoxicity were cell-type selective as serum exposure did not adversely affect microvascular endothelial cell viability but resulted in endothelial activation and a procoagulant state.

CONCLUSION: These results provide direct evidence that inflammatory cytokines are at least in part responsible for the cardiovascular damage seen in COVID-19 and characterise the downstream activated pathways in human cardiomyocytes. The serum signature of patients with severe disease indicates possible targets for therapeutic intervention.

PMID:38041432 | DOI:10.1093/cvr/cvad174

An attacin antimicrobial peptide, Hill_BB_C10074, from Hermetia illucens with anti-Pseudomonas aeruginosa activity

Fri, 01/12/2023 - 11:00

BMC Microbiol. 2023 Dec 1;23(1):378. doi: 10.1186/s12866-023-03131-1.


BACKGROUND: There is a global need to develop new therapies to treat infectious diseases and tackle the rise in antimicrobial resistance. To date, the larvae of the Black Solider Fly, Hermetia illucens, have the largest repertoire of antimicrobial peptides derived from insects. Antimicrobial peptides are of particular interest in the exploration of alternative antimicrobials due to their potent action and reduced propensity to induce resistance compared with more traditional antibiotics.

RESULTS: The predicted attacin from H. illucens, Hill_BB_C10074, was first identified in the transcriptome of H. illucens populations that had been fed a plant-oil based diet. In this study, recombinant Hill_BB_C10074 (500 µg/mL), was found to possess potent antimicrobial activity against the serious Gram-negative pathogen, Pseudomonas aeruginosa. Sequence and structural homology modelling predicted that Hill_BB_C10074 formed a homotrimeric complex that may form pores in the Gram-negative bacterial outer membrane. In vitro experiments defined the antimicrobial action of Hill_BB_C10074 against P. aeruginosa and transmission electron microscopy and electrochemical impedance spectroscopy confirmed the outer membrane disruptive power of Hill_BB_C10074 which was greater than the clinically relevant antibiotic, polymyxin B.

CONCLUSIONS: Combining predictive tools with in vitro approaches, we have characterised Hill_BB_C10074 as an important insect antimicrobial peptide and promising candidate for the future development of clinical antimicrobials.

PMID:38036998 | DOI:10.1186/s12866-023-03131-1

AlphaFold predictions are valuable hypotheses and accelerate but do not replace experimental structure determination

Thu, 30/11/2023 - 11:00

Nat Methods. 2023 Nov 30. doi: 10.1038/s41592-023-02087-4. Online ahead of print.


Artificial intelligence-based protein structure prediction methods such as AlphaFold have revolutionized structural biology. The accuracies of these predictions vary, however, and they do not take into account ligands, covalent modifications or other environmental factors. Here, we evaluate how well AlphaFold predictions can be expected to describe the structure of a protein by comparing predictions directly with experimental crystallographic maps. In many cases, AlphaFold predictions matched experimental maps remarkably closely. In other cases, even very high-confidence predictions differed from experimental maps on a global scale through distortion and domain orientation, and on a local scale in backbone and side-chain conformation. We suggest considering AlphaFold predictions as exceptionally useful hypotheses. We further suggest that it is important to consider the confidence in prediction when interpreting AlphaFold predictions and to carry out experimental structure determination to verify structural details, particularly those that involve interactions not included in the prediction.

PMID:38036854 | DOI:10.1038/s41592-023-02087-4

Placental Streptococcus agalactiae DNA is associated with neonatal unit admission and foetal pro-inflammatory cytokines in term infants

Wed, 29/11/2023 - 11:00

Nat Microbiol. 2023 Dec;8(12):2338-2348. doi: 10.1038/s41564-023-01528-2. Epub 2023 Nov 29.


Streptococcus agalactiae (Group B Streptococcus; GBS) is a common cause of sepsis in neonates. Previous work detected GBS DNA in the placenta in ~5% of women before the onset of labour, but the clinical significance of this finding is unknown. Here we re-analysed this dataset as a case control study of neonatal unit (NNU) admission. Of 436 infants born at term (≥37 weeks of gestation), 7/30 with placental GBS and 34/406 without placental GBS were admitted to the NNU (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.3-7.8). We then performed a validation study using non-overlapping subjects from the same cohort. This included a further 239 cases of term NNU admission and 686 term controls: 16/36 with placental GBS and 223/889 without GBS were admitted to the NNU (OR 2.4, 95% CI 1.2-4.6). Of the 36 infants with placental GBS, 10 were admitted to the NNU with evidence of probable but culture-negative sepsis (OR 4.8, 95% CI 2.2-10.3), 2 were admitted with proven GBS sepsis (OR 66.6, 95% CI 7.3-963.7), 6 were admitted and had chorioamnionitis (inflammation of the foetal membranes) (OR 5.3, 95% CI 2.0-13.4), and 5 were admitted and had funisitis (inflammation of the umbilical cord) (OR 6.7, 95% CI 12.5-17.7). Foetal cytokine storm (two or more pro-inflammatory cytokines >10 times median control levels in umbilical cord blood) was present in 36% of infants with placental GBS DNA and 4% of cases where the placenta was negative (OR 14.2, 95% CI 3.6-60.8). Overall, ~1 in 200 term births had GBS detected in the placenta, which was associated with infant NNU admission and morbidity.

PMID:38030897 | DOI:10.1038/s41564-023-01528-2

Associative pyridinium electrolytes for air-tolerant redox flow batteries

Wed, 29/11/2023 - 11:00

Nature. 2023 Nov;623(7989):949-955. doi: 10.1038/s41586-023-06664-7. Epub 2023 Nov 29.


Pyridinium electrolytes are promising candidates for flow-battery-based energy storage1-4. However, the mechanisms underlying both their charge-discharge processes and overall cycling stability remain poorly understood. Here we probe the redox behaviour of pyridinium electrolytes under representative flow battery conditions, offering insights into air tolerance of batteries containing these electrolytes while providing a universal physico-chemical descriptor of their reversibility. Leveraging a synthetic library of extended bispyridinium compounds, we track their performance over a wide range of potentials and identify the singlet-triplet free energy gap as a descriptor that successfully predicts the onset of previously unidentified capacity fade mechanisms. Using coupled operando nuclear magnetic resonance and electron paramagnetic resonance spectroscopies5,6, we explain the redox behaviour of these electrolytes and determine the presence of two distinct regimes (narrow and wide energy gaps) of electrochemical performance. In both regimes, we tie capacity fade to the formation of free radical species, and further show that π-dimerization plays a decisive role in suppressing reactivity between these radicals and trace impurities such as dissolved oxygen. Our findings stand in direct contrast to prevailing views surrounding the role of π-dimers in redox flow batteries1,4,7-11 and enable us to efficiently mitigate capacity fade from oxygen even on prolonged (days) exposure to air. These insights pave the way to new electrolyte systems, in which reactivity of reduced species is controlled by their propensity for intra- and intermolecular pairing of free radicals, enabling operation in air.

PMID:38030777 | DOI:10.1038/s41586-023-06664-7

Modelling local and general quantum mechanical properties with attention-based pooling

Wed, 29/11/2023 - 11:00

Commun Chem. 2023 Nov 29;6(1):262. doi: 10.1038/s42004-023-01045-7.


Atom-centred neural networks represent the state-of-the-art for approximating the quantum chemical properties of molecules, such as internal energies. While the design of machine learning architectures that respect chemical principles has continued to advance, the final atom pooling operation that is necessary to convert from atomic to molecular representations in most models remains relatively undeveloped. The most common choices, sum and average pooling, compute molecular representations that are naturally a good fit for many physical properties, while satisfying properties such as permutation invariance which are desirable from a geometric deep learning perspective. However, there are growing concerns that such simplistic functions might have limited representational power, while also being suboptimal for physical properties that are highly localised or intensive. Based on recent advances in graph representation learning, we investigate the use of a learnable pooling function that leverages an attention mechanism to model interactions between atom representations. The proposed pooling operation is a drop-in replacement requiring no changes to any of the other architectural components. Using SchNet and DimeNet++ as starting models, we demonstrate consistent uplifts in performance compared to sum and mean pooling and a recent physics-aware pooling operation designed specifically for orbital energies, on several datasets, properties, and levels of theory, with up to 85% improvements depending on the specific task.

PMID:38030692 | DOI:10.1038/s42004-023-01045-7

More than just a gel: the extracellular matrixome of <em>Pseudomonas aeruginosa</em>

Wed, 29/11/2023 - 11:00

Front Mol Biosci. 2023 Nov 13;10:1307857. doi: 10.3389/fmolb.2023.1307857. eCollection 2023.


Armed with an arsenal of protein secretion systems, antibiotic efflux pumps, and the occasional proclivity for explosive self-destruction, Pseudomonas aeruginosa has become a model for the study of bacterial pathogenesis and biofilm formation. There is accruing evidence to suggest that the biofilm matrix-the bioglue that holds the structure together-acts not only in a structural capacity, but is also a molecular "net" whose function is to capture and retain certain secreted products (including proteins and small molecules). In this perspective, we argue that the biofilm matrixome is a distinct extracellular compartment, and one that is differentiated from the bulk secretome. Some of the points we raise are deliberately speculative, but are becoming increasingly accessible to experimental investigation.

PMID:38028553 | PMC:PMC10679415 | DOI:10.3389/fmolb.2023.1307857

Molecular epidemiology of <em>Streptococcus agalactiae</em> in non-pregnant populations: a systematic review

Wed, 29/11/2023 - 11:00

Microb Genom. 2023 Nov;9(11). doi: 10.1099/mgen.0.001140.


Streptococcus agalactiae (group B Streptococcus, GBS) has recently emerged as an important pathogen among adults. However, it is overlooked in this population, with all global efforts being directed towards its containment among pregnant women and neonates. This systematic review assessed the molecular epidemiology and compared how the lineages circulating among non-pregnant populations relate to those of pregnant and neonatal populations worldwide. A systematic search was performed across nine databases from 1 January 2000 up to and including 20 September 2021, with no language restrictions. The Joanna Briggs Institute (JBI) Prevalence Critical Appraisal Tool (PCAT) was used to assess the quality of included studies. The global population structure of GBS from the non-pregnant population was analysed using in silico typing and phylogenetic reconstruction tools. Twenty-four articles out of 13 509 retrieved across 9 databases were eligible. Most studies were conducted in the World Health Organization European region (12/24, 50 %), followed by the Western Pacific region (6/24, 25 %) and the Americas region (6/24, 25 %). Serotype V (23%, 2310/10240) and clonal complex (CC) 1 (29 %, 2157/7470) were the most frequent serotype and CC, respectively. The pilus island PI1 : PI2A combination (29 %, 3931/13751) was the most prevalent surface protein gene, while the tetracycline resistance tetM (55 %, 5892/10624) was the leading antibiotic resistance gene. This study highlights that, given the common serotype distribution identified among non-pregnant populations (V, III, Ia, Ib, II and IV), vaccines including these six serotypes will provide broad coverage. The study indicates advanced molecular epidemiology studies, especially in resource-constrained settings for evidence-based decisions. Finally, the study shows that considering all at-risk populations in an inclusive approach is essential to ensure the sustainable containment of GBS.

PMID:38019122 | DOI:10.1099/mgen.0.001140

Durability of cross-neutralizing antibodies 5.5 months after bivalent COVID-19 booster

Tue, 28/11/2023 - 11:00

J Infect Dis. 2023 Nov 28:jiad472. doi: 10.1093/infdis/jiad472. Online ahead of print.


We analyzed neutralizing antibodies in samples from ancestral+BA.1 and ancestral+BA.4/5 boosted individuals, collected around 5.5 months after booster. Titers of neutralizing antibodies generally decreased compared to a time point early after the bivalent booster immunization. This was more pronounced for individuals without infection history and for recently emerged omicron variants.

PMID:38016020 | DOI:10.1093/infdis/jiad472

Resurrection of 2'-5'-oligoadenylate synthetase 1 (OAS1) from the ancestor of modern horseshoe bats blocks SARS-CoV-2 replication

Tue, 28/11/2023 - 11:00

PLoS Biol. 2023 Nov 28;21(11):e3002398. doi: 10.1371/journal.pbio.3002398. eCollection 2023 Nov.


The prenylated form of the human 2'-5'-oligoadenylate synthetase 1 (OAS1) protein has been shown to potently inhibit the replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. However, the OAS1 orthologue in the horseshoe bats (superfamily Rhinolophoidea), the reservoir host of SARS-related coronaviruses (SARSr-CoVs), has lost the prenylation signal required for this antiviral activity. Herein, we used an ancestral state reconstruction approach to predict and reconstitute in vitro, the most likely OAS1 protein sequence expressed by the Rhinolophoidea common ancestor prior to its prenylation loss (RhinoCA OAS1). We exogenously expressed the ancient bat protein in vitro to show that, unlike its non-prenylated horseshoe bat descendants, RhinoCA OAS1 successfully blocks SARS-CoV-2 replication. Using protein structure predictions in combination with evolutionary hypothesis testing methods, we highlight sites under unique diversifying selection specific to OAS1's evolution in the Rhinolophoidea. These sites are located near the RNA-binding region and the C-terminal end of the protein where the prenylation signal would have been. Our results confirm that OAS1 prenylation loss at the base of the Rhinolophoidea clade ablated the ability of OAS1 to restrict SARSr-CoV replication and that subsequent evolution of the gene in these bats likely favoured an alternative function. These findings can advance our understanding of the tightly linked association between SARSr-CoVs and horseshoe bats.

PMID:38015855 | DOI:10.1371/journal.pbio.3002398

Author Correction: A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis

Mon, 27/11/2023 - 11:00

Nat Commun. 2023 Nov 27;14(1):7751. doi: 10.1038/s41467-023-43699-w.


PMID:38012189 | DOI:10.1038/s41467-023-43699-w

Commensal Neisseria cinerea outer membrane vesicles as a platform for the delivery of meningococcal and gonococcal antigens to the immune system

Sun, 26/11/2023 - 11:00

Vaccine. 2023 Nov 25:S0264-410X(23)01378-6. doi: 10.1016/j.vaccine.2023.11.034. Online ahead of print.


An affordable, accessible, and broadly protective vaccine is required to tackle the re-occurring bacterial meningococcal epidemics in Sub-Saharan Africa as well as an effective control of multi-drug resistant strains of gonococcus. Outer membrane vesicles (OMVs) secreted from Gram-negative bacteria represent an attractive platform for antigen delivery to the immune system and therefore for development of multi-component vaccines. In this study, we describe the generation of modified OMVs (mOMVs) from commensal biosafety-level 1 (BSL-1) Neisseria cinerea ATCC® 14685TM, which is phylogenetically close to the pathogenic bacteria Neisseria meningitidis and Neisseria gonorrhoeae. mOMVs were prepared from N. cinerea engineered to express heterologous antigens from N. meningitidis (factor H binding protein (fHbp) and Neisseria Heparin Binding Antigen (NHBA-2)) and from N. gonorrhoeae (NHBA-542). Mice immunised with the mOMVs produced antibodies against fHbp and NHBA. The work indicates that mOMV from N. cinerea can be used as a platform to induce immune responses against antigens involved in the protective immune response against meningococcal and gonococcal diseases.

PMID:38008665 | DOI:10.1016/j.vaccine.2023.11.034

A robust mRNA signature obtained via recursive ensemble feature selection predicts the responsiveness of omalizumab in moderate-to-severe asthma

Sat, 25/11/2023 - 11:00

Clin Transl Allergy. 2023 Nov;13(11):e12306. doi: 10.1002/clt2.12306.


BACKGROUND: Not being well controlled by therapy with inhaled corticosteroids and long-acting β2 agonist bronchodilators is a major concern for severe-asthma patients. The current treatment option for these patients is the use of biologicals such as anti-IgE treatment, omalizumab, as an add-on therapy. Despite the accepted use of omalizumab, patients do not always benefit from it. Therefore, there is a need to identify reliable biomarkers as predictors of omalizumab response.

METHODS: Two novel computational algorithms, machine-learning based Recursive Ensemble Feature Selection (REFS) and rule-based algorithm Logic Explainable Networks (LEN), were used on open accessible mRNA expression data from moderate-to-severe asthma patients to identify genes as predictors of omalizumab response.

RESULTS: With REFS, the number of features was reduced from 28,402 genes to 5 genes while obtaining a cross-validated accuracy of 0.975. The 5 responsiveness predictive genes encode the following proteins: Coiled-coil domain- containing protein 113 (CCDC113), Solute Carrier Family 26 Member 8 (SLC26A), Protein Phosphatase 1 Regulatory Subunit 3D (PPP1R3D), C-Type lectin Domain Family 4 member C (CLEC4C) and LOC100131780 (not annotated). The LEN algorithm found 4 identical genes with REFS: CCDC113, SLC26A8 PPP1R3D and LOC100131780. Literature research showed that the 4 identified responsiveness predicting genes are associated with mucosal immunity, cell metabolism, and airway remodeling.

CONCLUSION AND CLINICAL RELEVANCE: Both computational methods show 4 identical genes as predictors of omalizumab response in moderate-to-severe asthma patients. The obtained high accuracy indicates that our approach has potential in clinical settings. Future studies in relevant cohort data should validate our computational approach.

PMID:38006387 | DOI:10.1002/clt2.12306

LUBAC is required for RIG-I sensing of RNA viruses

Fri, 24/11/2023 - 11:00

Cell Death Differ. 2023 Nov 24. doi: 10.1038/s41418-023-01233-x. Online ahead of print.


The ability of cells to mount an interferon response to virus infections depends on intracellular nucleic acid sensing pattern recognition receptors (PRRs). RIG-I is an intracellular PRR that binds short double-stranded viral RNAs to trigger MAVS-dependent signalling. The RIG-I/MAVS signalling complex requires the coordinated activity of multiple kinases and E3 ubiquitin ligases to activate the transcription factors that drive type I and type III interferon production from infected cells. The linear ubiquitin chain assembly complex (LUBAC) regulates the activity of multiple receptor signalling pathways in both ligase-dependent and -independent ways. Here, we show that the three proteins that constitute LUBAC have separate functions in regulating RIG-I signalling. Both HOIP, the E3 ligase capable of generating M1-ubiquitin chains, and LUBAC accessory protein HOIL-1 are required for viral RNA sensing by RIG-I. The third LUBAC component, SHARPIN, is not required for RIG-I signalling. These data cement the role of LUBAC as a positive regulator of RIG-I signalling and as an important component of antiviral innate immune responses.

PMID:38001254 | DOI:10.1038/s41418-023-01233-x

An integrated model for pre- and post-harvest aflatoxin contamination in maize

Sun, 19/11/2023 - 11:00

NPJ Sci Food. 2023 Nov 18;7(1):60. doi: 10.1038/s41538-023-00238-7.


Aflatoxin contamination caused by colonization of maize by Aspergillus flavus continues to pose a major human and livestock health hazard in the food chain. Increasing attention has been focused on the development of models to predict risk and to identify effective intervention strategies. Most risk prediction models have focused on elucidating weather and site variables on the pre-harvest dynamics of A. flavus growth and aflatoxin production. However fungal growth and toxin accumulation continue to occur after harvest, especially in countries where storage conditions are limited by logistical and cost constraints. In this paper, building on previous work, we introduce and test an integrated meteorology-driven epidemiological model that covers the entire supply chain from planting to delivery. We parameterise the model using approximate Bayesian computation with monthly time-series data over six years for contamination levels of aflatoxin in daily shipments received from up to three sourcing regions at a high-volume maize processing plant in South Central India. The time series for aflatoxin levels from the parameterised model successfully replicated the overall profile, scale and variance of the historical aflatoxin datasets used for fitting and validation. We use the model to illustrate the dynamics of A. flavus growth and aflatoxin production during the pre- and post-harvest phases in different sourcing regions, in short-term predictions to inform decision making about sourcing supplies and to compare intervention strategies to reduce the risks of aflatoxin contamination.

PMID:37980424 | DOI:10.1038/s41538-023-00238-7

Exploiting genomics for antimicrobial resistance surveillance at One Health interfaces

Fri, 17/11/2023 - 11:00

Lancet Microbe. 2023 Nov 14:S2666-5247(23)00284-7. doi: 10.1016/S2666-5247(23)00284-7. Online ahead of print.


The intersection of human, animal, and ecosystem health at One Health interfaces is recognised as being of key importance in the evolution and spread of antimicrobial resistance (AMR) and represents an important, and yet rarely realised opportunity to undertake vital AMR surveillance. A working group of international experts in pathogen genomics, AMR, and One Health convened to take part in a workshop series and online consultation focused on the opportunities and challenges facing genomic AMR surveillance in a range of settings. Here we outline the working group's discussion of the potential utility, advantages of, and barriers to, the implementation of genomic AMR surveillance at One Health interfaces and propose a series of recommendations for addressing these challenges. Embedding AMR surveillance at One Health interfaces will require the development of clear beneficial use cases, especially in low-income and middle-income countries. Evidence of directionality, risks to human and animal health, and potential trade implications were also identified by the working group as key issues. Addressing these challenges will be vital to enable genomic surveillance technology to reach its full potential for assessing the risk of transmission of AMR between the environment, animals, and humans at One Health interfaces.

PMID:37977165 | DOI:10.1016/S2666-5247(23)00284-7

Evidence review and recommendations for the implementation of genomics for antimicrobial resistance surveillance: reports from an international expert group

Fri, 17/11/2023 - 11:00

Lancet Microbe. 2023 Nov 14:S2666-5247(23)00281-1. doi: 10.1016/S2666-5247(23)00281-1. Online ahead of print.


Nearly a century after the beginning of the antibiotic era, which has been associated with unparalleled improvements in human health and reductions in mortality associated with infection, the dwindling pipeline for new antibiotic classes coupled with the inevitable spread of antimicrobial resistance (AMR) poses a major global challenge. Historically, surveillance of bacteria with AMR typically relied on phenotypic analysis of isolates taken from infected individuals, which provides only a low-resolution view of the epidemiology behind an individual infection or wider outbreak. Recent years have seen increasing adoption of powerful new genomic technologies with the potential to revolutionise AMR surveillance by providing a high-resolution picture of the AMR profile of the bacteria causing infections and providing real-time actionable information for treating and preventing infection. However, many barriers remain to be overcome before genomic technologies can be adopted as a standard part of routine AMR surveillance around the world. Accordingly, the Surveillance and Epidemiology of Drug-resistant Infections Consortium convened an expert working group to assess the benefits and challenges of using genomics for AMR surveillance. In this Series, we detail these discussions and provide recommendations from the working group that can help to realise the massive potential benefits for genomics in surveillance of AMR.

PMID:37977164 | DOI:10.1016/S2666-5247(23)00281-1

Innovations in genomic antimicrobial resistance surveillance

Fri, 17/11/2023 - 11:00

Lancet Microbe. 2023 Nov 14:S2666-5247(23)00285-9. doi: 10.1016/S2666-5247(23)00285-9. Online ahead of print.


Whole-genome sequencing of antimicrobial-resistant pathogens is increasingly being used for antimicrobial resistance (AMR) surveillance, particularly in high-income countries. Innovations in genome sequencing and analysis technologies promise to revolutionise AMR surveillance and epidemiology; however, routine adoption of these technologies is challenging, particularly in low-income and middle-income countries. As part of a wider series of workshops and online consultations, a group of experts in AMR pathogen genomics and computational tool development conducted a situational analysis, identifying the following under-used innovations in genomic AMR surveillance: clinical metagenomics, environmental metagenomics, gene or plasmid tracking, and machine learning. The group recommended developing cost-effective use cases for each approach and mapping data outputs to clinical outcomes of interest to justify additional investment in capacity, training, and staff required to implement these technologies. Harmonisation and standardisation of methods, and the creation of equitable data sharing and governance frameworks, will facilitate successful implementation of these innovations.

PMID:37977163 | DOI:10.1016/S2666-5247(23)00285-9