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X-AMR, a pop-up journal

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X-AMR, a pop-up journal
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Antimicrobial resistance (AMR) is a cross-disciplinary issue, with ground-breaking studies currently bringing together clinicians and modellers, veterinary and soil scientists, microbiologists and anthropologists. Yet finding a home for the unique publications from this research is difficult. The Microbiology Society is providing such a home with a new pop-up journal for cross-disciplinary research on antimicrobial resistance: X-AMR.

We invite submissions in the form of research papers, mini-reviews or commentaries. For more information on X-AMR, including how to submit your article, see our FAQs page.

Included in this collection are a host of antimicrobial resistance papers already published across our portfolio. The latest X-AMR articles will appear as and when they are published. Read our Guest Editors' introductory Editorial here.

Collection Contents

11 results

    • Multi-step genomic dissection of a suspected intra-hospital Helicobacter cinaedi outbreak

      Helicobacter cinaedi is an emerging pathogen causing bacteraemia and cellulitis. Nosocomial transmission of this microbe has been described, but detailed molecular-epidemiological analyses have not been performed. Here, we describe the results of a multi-step genome-wide phylogenetic analysis of a suspected intra-hospital outbreak of H. cinaedi that occurred in a hospital in Japan. The outbreak was recognized by the infectious control team (ICT) of the hospital as a sudden increase in H. cinaedi bacteraemia. ICT defined this outbreak case based on 16S rRNA sequence data and epidemiological information, but were unable to determine the source and route of the infections. We therefore re-investigated this case using whole-genome sequencing (WGS). We first performed a species-wide analysis using publicly available genome sequences to understand the level of genomic diversity of this under-studied species. The clusters identified were then separately analysed using the genome sequence of a representative strain in each cluster as a reference. These analyses provided a high-level phylogenetic resolution of each cluster, identified a confident set of outbreak isolates, and discriminated them from other closely related but distinct clones, which were locally circulating and invaded the hospital during the same period. By considering the epidemiological data, possible strain transmission chains were inferred, which highlighted the role of asymptomatic carriers or environmental contamination. The emergence of a subclone with increased resistance to fluoroquinolones in the outbreak was also recognized. Our results demonstrate the impact of the use of a closely related genome as a reference to maximize the power of WGS.

    • A mutation in anti-sigma factor MAB_3542c may be responsible for tigecycline resistance in Mycobacterium abscessus

      In this study, we characterized 7C, a spontaneous mutant selected from tigecycline-susceptible Mycobacterium abscessus ATCC 19977. Whole-genome sequencing (WGS) was used to identify possible resistance determinants in this mutant. Compared to the wild-type, 7C demonstrated resistance to tigecycline as well as cross-resistance to imipenem, and had a slightly retarded growth rate. WGS and subsequent biological verifications showed that these phenotypes were caused by a point mutation in MAB_3542c, which encodes an RshA-like protein. In Mycobacterium tuberculosis, RshA is an anti-sigma factor that negatively regulates the heat/oxidative stress response mechanisms. The MAB_3542c mutation may represent a novel determinant of tigecycline resistance. We hypothesize that this mutation may dysregulate the stress-response pathways which have been shown to be linked to antibiotic resistance in previous studies.

    • Mechanisms of carbapenem resistance in Acinetobacter pittii and Acinetobacter nosocomialis isolates from Thailand

      Purpose. The emergence of carbapenem resistance in non-baumannii Acinetobacter has increased in clinical settings worldwide. We investigated the prevalence and mechanisms of carbapenem resistance in A. pittii and A. nosocomialis Thai isolates.

      Methodology. Acinetobacter calcoaceticus–Acinetobacter baumannii (Acb) complex isolates were identified by gyrB mulitplex PCR. Carbapenem susceptibilities were studied by the agar dilution method and carbapenemase genes were detected by multiplex PCR. Reductions of the outer membrane proteins (OMPs) were evaluated by SDS-PAGE. Overexpressions of efflux pumps were detected by using efflux pump inhibitors and RT-PCR.

      Results. Of the 346 Acb isolates, 22 and 19 were A. pittii and A. nosocomialis, respectively. The carbapenem resistance rates were 22.7 % in A. pittii and 26.3 % in A. nosocomialis. Three carbapenem-resistant A. pittii carried bla OXA-23. One carbapenem-resistant A. pittii harboured bla OXA-58, while another isolate co-harboured bla OXA-58 and bla IMP-14a. bla OXA-58 was also found in three carbapenem-susceptible A. pittii. Five carbapenem-resistant A. nosocomialis carried bla OXA-23. Eighteen A. pittii isolates carried bla OXA-213-like. Reduced OMPs were found in carbapenem-resistant and -susceptible A. pittii carrying bla OXA-58, but were not detected in carbapenem-resistant A. nosocomialis isolates. Overexpression of adeE was found in carbapenem-resistant A. pittii. No efflux pump genes were present in carbapenem-resistant A. nosocomialis.

      Conclusion. The major mechanisms of carbapenem resistance in A. pittii and A. nosocomialis were the production of OXA-23 and OXA-58. Overexpression of adeE played a role in carbapenem resistance in A. pittii. Since bla OXA-58 was found in carbapenem-susceptible A. pittii, using carbapenems in the treatment of A. pittii infection should be considered.

    • mlplasmids: a user-friendly tool to predict plasmid- and chromosome-derived sequences for single species

      Assembly of bacterial short-read whole-genome sequencing data frequently results in hundreds of contigs for which the origin, plasmid or chromosome, is unclear. Complete genomes resolved by long-read sequencing can be used to generate and label short-read contigs. These were used to train several popular machine learning methods to classify the origin of contigs from Enterococcus faecium, Klebsiella pneumoniae and Escherichia coli using pentamer frequencies. We selected support-vector machine (SVM) models as the best classifier for all three bacterial species (F1-score E. faecium=0.92, F1-score K. pneumoniae=0.90, F1-score E. coli=0.76), which outperformed other existing plasmid prediction tools using a benchmarking set of isolates. We demonstrated the scalability of our models by accurately predicting the plasmidome of a large collection of 1644 E. faecium isolates and illustrate its applicability by predicting the location of antibiotic-resistance genes in all three species. The SVM classifiers are publicly available as an R package and graphical-user interface called ‘mlplasmids’. We anticipate that this tool may significantly facilitate research on the dissemination of plasmids encoding antibiotic resistance and/or contributing to host adaptation.

    • MinION nanopore sequencing identifies the position and structure of bacterial antibiotic resistance determinants in a multidrug-resistant strain of enteroaggregative Escherichia coli

      The aim of this study was to use single-molecule, nanopore sequencing to explore the genomic environment of the resistance determinants in a multidrug-resistant (MDR) strain of enteroaggregative Escherichia coli serotype O51 : H30, sequence type (ST) 38. Sequencing was performed on the MinION Flow cell MIN-106 R9.4. Nanopore raw FAST5 reads were base-called using Albacore v1.2.1, converted to FASTA and FASTQ formats using Poretools v0.6.0, and assembled using Unicycler v0.4.2, combining the long-read sequencing data with short-read data produced by Illumina sequencing. The genome was interrogated against an antimicrobial resistance (AMR) gene reference database using blast. The majority of the 12 AMR determinants identified were clustered together on the chromosome at three separate locations flanked by integrases and/or insertion elements [region 1 –catA, bla OXA-1, aac(6′)-Ib-cr, tetA and bla CTX-M-15; region 2 – dfrA1 and aadA1; region 3 – catA, bla TEM-1, tetA and sul2]. AMR determinants located outside these three regions were a chromosomally encoded bla CMY-16, mutations in gyrA and parC, and two plasmid-encoded AMR determinants, bla OXA-181 and qnrS1 located on the same IncX3 plasmid. Long-read analysis of whole genome sequencing data identified mobile genetic elements on which AMR determinants were located and revealed the combination of different AMR determinants co-located on the same mobile element. These data contribute to a better understanding of the transmission of co-located AMR determinants in MDR E. coli causing gastrointestinal and extra-intestinal infections.

    • Molecular determinants of Burkholderia pseudomallei BpeEF-OprC efflux pump expression

      Burkholderia pseudomallei, the cause of melioidosis, is intrinsically resistant to many antibiotics. Acquired multidrug resistance, including resistance to doxycycline and co-trimoxazole used for melioidosis eradication phase therapy, is mainly attributed to constitutive expression of the BpeEF-OprC efflux pump. Constitutive expression of this pump is caused by mutations affecting two highly similar LysR-type transcriptional regulators (LTTR), BpeT and BpeS, but their interaction with the regulatory region governing BpeEF-OprC expression has not yet been studied. The bpeE-bpeF-oprC genes are distally located in the llpE-bpeE-bpeF-oprC operon. The llpE gene encodes a putative lipase/esterase of unknown function. We show that in a bpeT mutant llpE is constitutively co-transcribed with bpeE-bpeF-oprC. As expected from previous studies with B. cenocepacia, deletion of llpE does not affect antibiotic efflux. Using transcriptional bpeE′-lacZ fusions, we demonstrate that the 188 bp bpeT-llpE intergenic region located between bpeT and the llpE-bpeE-bpeF-oprC operon contains regulatory elements needed for control of bpeT and llpE-bpeE-bpeF-oprC operon expression. By native polyacrylamide gel electrophoresis and electrophoretic mobility shift assays with purified recombinant BpeT and BpeS proteins, we show BpeT and BpeS form oligomers that share a 14 bp binding site overlapping the essential region required for llpE-bpeE-bpeF-oprC expression. The binding site contains the conserved T-N11-A LTTR box motif involved in binding of LysR proteins, which in concert with two other possible LTTR boxes may mediate BpeT and BpeS regulation of BpeEF-OprC expression. These studies form the basis for further investigation of BpeEF-OprC expression and regulation at the molecular level by yet unknown external stimuli.

    • Multicenter assessment of the rapid Unyvero Blood Culture molecular assay

      Purpose. Bloodstream infections remain an important cause of morbidity and mortality. Rapid diagnosis can reduce the time from empiric antimicrobial therapy to targeted therapy and improve patient outcomes.

      Methodology. The fully automated Unyvero Blood Culture (BCU) Application (Curetis GmbH) can identify a broad panel of pathogens (36 analytes covering over 50 pathogens) and 16 antibiotic resistance gene markers simultaneously in about 5 h. The assay was evaluated in three clinical laboratories in comparison to routine microbiological procedures.

      Results. A total of 207 blood cultures were included in the study, and 90.5 % of the species identified by culture were covered by the Unyvero BCU panel with an overall sensitivity of 96.8 % and specificity of 99.8 %. The time to result was reduced on average by about 34 h. The assay accurately identified 95 % of the species, including 158/164 monomicrobial and 7/9 polymicrobial cultures. The Unyvero BCU Cartridge detected a large number of resistance markers including mecA (n=57), aac(6′)aph(2′′) (n=40), one vanB resistance gene, and six instances of bla CTX-M.

      Conclusion. The Unyvero BCU Application provided fast, reliable results, while significantly improving turnaround time in blood culture diagnostics.

    • A manganese photosensitive tricarbonyl molecule [Mn(CO)(tpa-κ )]Br enhances antibiotic efficacy in a multi-drug-resistant

      Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)(tpa-κ )]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)(tpa-κ )]Br also potentiates the action of doxycycline, resulting in reduced expression of which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)(tpa-κ )]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)(tpa-κ )]Br.

    • Marsupial and monotreme cathelicidins display antimicrobial activity, including against methicillin-resistant

      With the growing demand for new antibiotics to combat increasing multi-drug resistance, a family of antimicrobial peptides known as cathelicidins has emerged as potential candidates. Expansions in cathelicidin-encoding genes in marsupials and monotremes are of specific interest as the peptides they encode have evolved to protect immunologically naive young in the harsh conditions of the pouch and burrow. Our previous work demonstrated that some marsupial and monotreme cathelicidins have broad-spectrum antibacterial activity and kill resistant bacteria, but the activity of many cathelicidins is unknown. To investigate associations between peptide antimicrobial activity and physiochemical properties, we tested 15 cathelicidin mature peptides from tammar wallaby, grey short-tailed opossum, platypus and echidna for antimicrobial activity against a range of bacterial and fungal clinical isolates. One opossum cathelicidin ModoCath4, tammar wallaby MaeuCath7 and echidna Taac-CATH1 had broad-spectrum antibacterial activity and killed methicillin-resistant However, antimicrobial activity was reduced in the presence of serum or whole blood, and non-specific toxicity was observed at high concentrations. The active peptides were highly charged, potentially increasing binding to microbial surfaces, and contained amphipathic helical structures, which may facilitate membrane permeabilisation. Peptide sequence homology, net charge, amphipathicity and alpha helical content did not correlate with antimicrobial activity. However active peptides contained a significantly higher percentage of cationic residues than inactive ones, which may be used to predict active peptides in future work. Along with previous studies, our results indicate that marsupial and monotreme cathelicidins show potential for development as novel therapeutics to combat increasing antimicrobial resistance.

    • Mechanisms of quinolone action and resistance: where do we stand?

      Quinolone antibiotics represent one of the most important classes of anti-infective agents and, although still clinically valuable, their use has been compromised by the increasing emergence of resistant strains, which has become a prevalent clinical problem. Quinolones act by inhibiting the activity of DNA gyrase and topoisomerase IV – two essential bacterial enzymes that modulate the chromosomal supercoiling required for critical nucleic acid processes. The acquisition of quinolone resistance is recognized to be multifactorial and complex. The main resistance mechanism consists of one or a combination of target-site gene mutations that alter the drug-binding affinity of target enzymes. However, other mechanisms such as mutations that lead to reduced intracellular drug concentrations, by either decreased uptake or increased efflux, and plasmid-encoded resistance genes producing either target protection proteins, drug-modifying enzymes or multidrug efflux pumps are known to contribute additively to quinolone resistance. The understanding of these different resistance mechanisms has improved significantly in recent years; however, many details remain to be clarified and the contribution of less-studied mechanisms still needs to be better elucidated in order to fully understand this phenotype.

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