Roger Simm

• Nadeem, Nudrat; Nadeem, Muhammad; Bostan, Nazish; Sattar, Sadia; Simm, Roger & Javed, Sundus (2025). Assessment of water quality and occurrence of multidrug-resistant clinically relevant bacteria in drinking water in the twin cities of Pakistan. Environmental Monitoring and Assessment. ISSN 0167-6369. 197(5). doi: 10.1007/s10661-025-13989-5. Full text in Research Archive Show summary

  Water filtration plants are a main source of drinking water for local populations in almost all big cities of Pakistan but these filtration plants are ineffective in eliminating contaminants from water. This study was conducted to evaluate water quality with specific focus on physicochemical parameters and bacterial contamination including occurrence of multidrug-resistant bacteria in drinking water collected from filtration plants ( N = 64) of the twin cities of Pakistan. Physicochemical parameters were analyzed following American Public Health Association standard guidelines and total coliform count was determined using membrane filtration method. Gram-negative bacteria were isolated and characterized in terms of species and antibiotic susceptibility. Elevated levels of total dissolved solids, nitrates, total coliforms, lead and copper were found in several samples. Multivariate correlation coefficient revealed significant positive correlation between nitrate levels and total coliform count in bacteriologically contaminated samples. Antibiotic resistance patterns revealed multidrug-resistant and extensively drug-resistant bacteria with high resistance against third generation cephalosporins. Our results highlight the urgent need for improved water filtration processes and regular monitoring to provide safe drinking water to the local community.

• Vevik, Kristina; Sribasgaran, Biramitha; Cai, Kun; Naemi, Ali-Oddin; Kaspersen, Håkon & Uhlig, Silvio [Show all 8 contributors for this article] (2025). TrkA of Streptococcus mitis CCUG31611 binds cyclic di-adenosine monophosphate and is required for growth in low potassium conditions. Microbiology (Reading). ISSN 1350-0872. 171(8). doi: 10.1099/mic.0.001597. Full text in Research Archive Show summary

  Cyclic di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger regulating many physiological processes in bacteria. In the oral commensal species Streptococcus mitis, c-di-AMP is involved in regulating metabolism, growth, colony morphology, chain length, biofilm formation and DNA stress tolerance. However, no c-di-AMP-regulated effector proteins have yet been characterized in S. mitis. In this study, we first show that a ΔcdaA mutant, unable to produce c-di-AMP, grows slowly under low environmental potassium conditions. Growth of the cdaA mutant was not restored by reintroducing cdaA in the original locus (KBcdaA). Whole-genome sequencing of multiple KBcdaA isolates revealed secondary mutations in a putative potassium transporter. The mutations were predicted to result in the truncation of the protein or the alteration of a conserved glycine residue essential for selective potassium uptake, disrupting protein function. A Δpde2 mutant overproducing c-di-AMP survived poorly under high environmental sodium concentrations. We then characterized the potassium transporter regulator protein TrkA. Biochemical analyses of the purified recombinant TrkA protein revealed that it specifically binds c-di-AMP with high affinity in vitro. Using deletion mutants of trkA, we demonstrate that TrkA is essential for growth under low environmental potassium conditions. Ultra-high-performance liquid chromatography coupled to tandem mass spectrometry revealed lower c-di-AMP concentration in the ΔtrkA mutant compared to the WT. This was not due to transcriptional regulation of the expression of the c-di-AMP turnover proteins CdaA, Pde1 or Pde2. C-di-AMP production is not affected by the extracellular potassium concentrations under the conditions tested. We also demonstrate a potential role of TrkA in UV stress tolerance but do not characterize the mechanism in this study.

• Ferrando, Maria Laura; Saluzzo, Francesca; Frederiksen, Rikki Franklin; Slettemeås, Jannice Schau; Urdahl, Anne Margrete & Simm, Roger [Show all 20 contributors for this article] (2025). Determination of Epidemiological Cut-off values for Narasin, Salinomycin, Lasalocid and Monensin in Enterococcus faecium. Journal of Antimicrobial Chemotherapy. ISSN 0305-7453. 80, p. 2361–2368. doi: 10.1093/jac/dkaf113. Full text in Research Archive Show summary

  Objectives To establish epidemiological cut-off values (ECOFFs) for the polyether ionophores narasin, salinomycin, lasalocid and monensin in Enterococcus faecium. Methods MICs were measured using the broth microdilution method according to ISO 20776-1 (2019). Method validation involved ≥10 replicates of antimicrobial susceptibility testing of Enterococcus faecalis ATCC 29212. A total of 182 E. faecium isolates from various sources were tested in five European laboratories. The ECOFFinder tool from EUCAST was used to establish the ECOFFs for 122 WT isolates, verified by PCR or WGS. Results Method validation showed consistency, with acceptable variation within ±1 2-fold dilution. The ECOFF for narasin was 0.5 mg/L, considerably below the current EUCAST ECOFF for E. faecium (ECOFF = 2 mg/L). Salinomycin and lasalocid ECOFFs were 1 and 2 mg/L, respectively. Strains carrying the previously identified narAB resistance genes clearly manifested a separate MIC distribution for narasin and salinomycin, but not for lasalocid, although a clear bias to the higher MIC values within the normal distribution could be observed. Monensin apparently displayed a broader MIC range (0.5–64 mg/L) with multiple modes, which precluded the establishment of an ECOFF for monensin. Conclusions The study yielded novel ECOFFs for distinguishing WT E. faecium strains for the key veterinary ionophores, providing a mainstay for a better understanding of ionophore resistance in enterococci.

• Prydz, Kristian; Simm, Roger; Davydova, Erna & Åsheim, Hans-Christian (2025). Ephrin-B1 regulates cell surface residency of heparan sulfate proteoglycans (HSPGs) and complexes with the HSPG CD44V3-10 and fibroblast growth factor receptors. Glycobiology. ISSN 0959-6658. 35(6). doi: 10.1093/glycob/cwaf020. Full text in Research Archive Show summary

  The ephrin family of membrane proteins mediate intracellular signalling as ligands of transmembrane Eph tyrosine kinase receptors during cell–cell interactions. Ephrin/Eph signalling regulates processes like cell migration and angiogenesis and is of particular importance during embryonic development. Ephrins-A3 and -B3 can also bind to cell surface-associated and soluble heparan sulfate proteoglycans (HSPGs) that also play important roles during early development. Here we show that ephrins-B1, -B2, and -B3 all can bind in cis to cell surface HSPGs, while only ephrin-B1 interacts with cell surface HSPGs in a way that retards HSPG endocytosis. Expressing ephrin-B1 in HEK293T cells, using polyethyleneimine (PEI) as transfection agent, increased cell surface levels of HSPGs which were detected by an anti-heparan sulfate (HS) antibody or by ephrin-B3-Fc binding. Ephrin-B1 in the plasma membrane seemed to retard PEI-induced HSPG internalisation and degradation. Binding of HSPGs by ephrin-B1 was observed for the human, mouse, xenopus, and zebrafish homologs, and did not require the cytoplasmic tail of ephrin-B1 that contains tyrosines shown to be involved in intracellular signalling. Furthermore, ephrin-B1 could bind the HSPG variant of CD44 (CD44V3–10), a complex that could further associate with fibroblast growth factor receptors (1 and 4) after co-expression with one of these receptors. In summary, our data indicate that ephrin-B1 can regulate cellular HSPG turnover and is able to form complexes of potential biological importance with CD44V3–10 and fibroblast growth factor receptors.

• Frederiksen, Rikki Franklin; Urdahl, Anne Margrete; Slettemeås, Jannice Schau; Granstad, Silje; Simm, Roger & Lagesen, Karin (2025). Genomic characterization of vancomycin-resistant enterococci in Norwegian poultry. PLOS ONE. 20(6). doi: 10.1371/journal.pone.0324789. Full text in Research Archive Show summary

  Vancomycin resistant enterococci (VRE) are a globally leading cause of nosocomial infections in humans, and a potential animal VRE reservoir, especially in poultry, is of concern. It has been suggested that the presence of VRE in broilers has been prolonged due to co-selection of narasin resistance (narAB genes) and vancomycin resistance (vanA genes), and that these genes may be present on the same plasmids. The aim of this study was to use whole genome sequencing to characterize and compare both the chromosomes and plasmids of VRE isolates from poultry in Norway, and to elucidate whether co-localisation of narAB and vanA genes on the same genetic elements, or clonal spread, could explain the persistence of VRE. A total of 30 VRE isolates from the years 2002–2013 were included, 23 from broiler flocks and seven from turkey flocks. WGS analyses showed that the isolates were genetically diverse with the number of SNPs ranging from 10 to 2807. The isolates belonged to 15 different sequence types, though all carried a plasmid similar to pVEF plasmids, and contained both vanA and narAB. A comparative gene analysis indicated that narAB is carried on a composite transposon, and that interspecies transfer of the plasmid between Enterococcus faecium and Enterococcus hirae may occur. The absence of transfer genes on the pVEF-like plasmids and their presence on a megaplasmid suggest that the megaplasmid probably act as a helper plasmid. Overall, the results support that the use of narasin in broilers may be a risk factor for a persistent reservoir of VRE in broilers.

• Uhlig, Silvio; Vevik, Kristina; Vyver, Joke Van De; Dragland, Inger Sofie; Grutle, Lene & Pain, Maria Ronessen [Show all 7 contributors for this article] (2025). Separation and Quantification of Cyclic di-AMP, -GMP, and Cyclic GAMP in Bacteria Using LC–MS/MS. Journal of Separation Science. ISSN 1615-9306. 48(5). doi: 10.1002/jssc.70157. Full text in Research Archive
• Uhlig, Silvio; Cai, Kun; Liskiewicz, Krystyna Anna; Pain, Maria Ronessen; Grutle, Lene & Røberg-Larsen, Hanne [Show all 7 contributors for this article] (2024). Profiling of cyclic di-adenyl and -guanyl nucleotides and their precursors and degradation products in bacteria using LC–MS/MS. Separation Science Plus (SSC plus). doi: 10.1002/sscp.202400039. Full text in Research Archive
• Hussain, Badra; Simm, Roger; Bueno, Jaime; Giannettou, Savvas; Naemi, Ali-Oddin & Lyngstadaas, Ståle Petter [Show all 7 contributors for this article] (2024). Biofouling on titanium implants: a novel formulation of poloxamer and peroxide for in situ removal of pellicle and multi-species oral biofilm. Regenerative Biomaterials. 11. doi: 10.1093/rb/rbae014. Full text in Research Archive Show summary

  Eradicating biofouling from implant surfaces is essential in treating peri-implant infections, as it directly addresses the microbial source for infection and inflammation around dental implants. This controlled laboratory study examines the effectiveness of the four commercially available debridement solutions (EDTA (Prefgel®), NaOCl (Perisolv®), H2O2 (Sigma-Aldrich), and Chlorhexidine (GUM® Paroex®)) in removing the acquired pellicle, preventing pellicle re-formation, and removing of a multi-species oral biofilm growing on a titanium implant surface, and compare the results with the effect of a novel formulation of a peroxide activated Poloxamer gel (Nubone® Clean). Evaluation of pellicle removal and re-formation was conducted using Scanning Electron Microscope (SEM), Energy Dispersive X-ray Spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS) to assess the surface morphology, elemental composition, and chemical surface composition. Hydrophilicity was assessed through contact angle measurements. The multi-species biofilm model included Streptococcus oralis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans, reflecting the natural oral microbiome's complexity. Biofilm biomass was quantified using safranin staining, biofilm viability was evaluated using confocal laser scanning microscopy, and SEM was used for morphological analyses of the biofilm. Results indicated that while no single agent completely eradicated the biofilm, the Poloxamer gel activated with H2O2 exhibited promising results. It minimised re-contamination of the pellicle by significantly lowering the contact angle, indicating enhanced hydrophilicity. This combination also showed a notable reduction in carbon contaminants, suggesting the effective removal of organic residues from the titanium surface, in addition to effectively reducing viable bacterial counts. In conclusion, the Poloxamer gel + H2O2 combination emerged as a promising chemical decontamination strategy for peri-implant diseases. It underlines the importance of tailoring treatment methods to the unique microbial challenges in peri-implant diseases and the necessity of combining chemical decontaminating strategies with established mechanical cleaning procedures for optimal management of peri-implant diseases.

• Frederiksen, Rikki Franklin; Slettemeås, Jannice Schau; Granstad, Silje; Lagesen, Karin; Pikkemaat, Mariel G. & Urdahl, Anne Margrete [Show all 7 contributors for this article] (2024). Polyether ionophore resistance in a one health perspective. Frontiers in Microbiology. 15(1347490), p. 1–11. doi: 10.3389/fmicb.2024.1347490. Full text in Research Archive Show summary

  Antimicrobial resistance is a major threat to human health and must be approached from a One Health perspective. Use of antimicrobials in animal husbandry can lead to dissemination and persistence of resistance in human pathogens. Polyether ionophores (PIs) have antimicrobial activities and are among the most extensively used feed additives for major production animals. Recent discoveries of genetically encoded PI resistance mechanisms and co-localization of resistance mechanisms against PIs and antimicrobials used in human medicine on transferrable plasmids, have raised concerns that use of PIs as feed additives bear potential risks for human health. This review summarizes the current knowledge on PI resistance and discusses the potential consequences of PI-usage as feed additives in a One Health perspective.

• Cimdins, Annika; Naemi, Ali-Oddin; Li, Fengyang; Simm, Roger & Römling, Ute (2023). Characterisation of Variants of Cyclic di-GMP Turnover Proteins Associated with Semi-Constitutive rdar Morphotype Expression in Commensal and Uropathogenic Escherichia coli Strains. Microorganisms. 11(8). doi: 10.3390/microorganisms11082048. Full text in Research Archive Show summary

  Expression of rdar (red, dry, and rough) colony morphology-based biofilm formation in Escherichia coli is highly variable. To investigate the molecular mechanisms of semi-constitutive rdar morphotype formation, we compared their cyclic di-GMP turnover protein content and variability to the highly regulated, temperature-dependent morphotype of the historical and modern ST10 isolates E. coli MG1655 and Fec10, respectively. Subsequently, we assessed the effects of cyclic di-GMP turnover protein variants of the EAL phosphodiesterases YcgG and YjcC and the horizontally transferred diguanylate cyclase DgcX on biofilm formation and motility. The two YcgG variants with truncations of the N-terminal CSS signaling domain were oppositely effective in targeting downregulation of rdar biofilm formation compared to the full-length reference protein. Expression of the C-terminal truncated variants YjcCFec67 and YjcCTob1 showed highly diminished apparent phosphodiesterase activity compared to the reference YjcCMG1655. For YjcCFec101, substitution of the C-terminus led to an apparently inactive enzyme. Overexpression of the diguanylate cyclase DgcX contributed to upregulation of cellulose biosynthesis but not to elevated expression of the major biofilm regulator csgD in the “classical” rdar-expressing commensal strain E. coli Fec10. Thus, the c-di-GMP regulating network is highly complex with protein variants displaying substantially different apparent enzymatic activities.

• Munir, Arooj; Marovic, Danijela; Nogueira, Liebert Parreiras; Simm, Roger; Naemi, Ali-Oddin & Landrø, Sander Marius [Show all 14 contributors for this article] (2022). Using Copper-Doped Mesoporous Bioactive Glass Nanospheres to Impart Anti-Bacterial Properties to Dental Composites. Pharmaceutics. 14(10). doi: 10.3390/pharmaceutics14102241. Full text in Research Archive Show summary

  Experimental dental resin composites containing copper-doped mesoporous bioactive glass nan-ospheres (Cu-MBGN) were developed to impart anti-bacterial properties. Increasing amounts of Cu-MBGN (0, 1, 5 and 10 wt%) were added to the BisGMA/TEGDMA resin matrix containing micro- and nano-fillers of inert glass, keeping the resin/filler ratio constant. Surface micromor-phology and elemental analysis were performed to evaluate the homogeneous distribution of filler particles. The study investigated the effects of Cu-MBGN on the degree of conversion, polymeri-zation shrinkage, porosity, ion release and anti-bacterial activity on S. mutans and A. naeslundii. Experimental materials containing Cu-MBGN showed a dose-dependent Cu release with an initial burst and a further increase after 28 days. The composite containing 10% Cu-MBGN had the best anti-bacterial effect on S. mutans, as evidenced by the lowest adherence of free-floating bacteria and biofilm formation. In contrast, the 45S5-containing materials had the highest S. mutans ad-herence. Ca release was highest in the bioactive control containing 15% 45S5, which correlated with the highest number of open porosities on the surface. Polymerization shrinkage was similar for all tested materials, ranging from 3.8 to 4.2%, while the degree of conversion was lower for Cu-MBGN materials. Cu-MBGN composites showed better anti-bacterial properties than compo-sites with 45S5 BG.

• Rørvik, Gro Herredsvela; Naemi, Ali-Oddin; Edvardsen, Per Kristian Thorén & Simm, Roger Gustav (2021). The c-di-AMP signaling system influences stress tolerance and biofilm formation of Streptococcus mitis. MicrobiologyOpen. 10(4), p. 1–15. doi: 10.1002/mbo3.1203. Full text in Research Archive Show summary

  Streptococcus mitis is a commensal bacterial species of the oral cavity, with the potential for opportunistic pathogenesis. For successful colonization, S. mitis must be able to adhere to surfaces of the oral cavity and survive and adapt to frequently changing environmental conditions. Cyclic-di-AMP (c-di-AMP) is a nucleotide second messenger, involved in the regulation of stress responses and biofilm formation in several bacterial species. Cyclic-di-AMP is produced by diadenylate cyclases and degraded by phosphodiesterases. We have previously shown that in S. mitis, one diadenylate cyclase (CdaA) and at least two phosphodiesterases (Pde1 and Pde2) regulate the intracellular concentration of c-di-AMP. In this study, we utilized S. mitis deletion mutants of cdaA, pde1, and pde2 to analyze the role of c-di-AMP signaling in various stress responses, biofilm formation, and adhesion to eukaryotic cells. Here, we demonstrate that the Δpde1 mutant displayed a tendency toward increased susceptibility to acetic acid at pH 4.0. Deletion of cdaA increases auto-aggregation of S. mitis but reduces biofilm formation on an abiotic surface. These phenotypes are more pronounced under acidic extracellular conditions. Inactivation of pde1 or pde2 reduced the tolerance to ciprofloxacin, and UV radiation and the Δpde1 mutant was more susceptible to Triton X-100, indicating a role for c-di-AMP signaling in responses to DNA damage and cell membrane perturbation. Finally, the Δpde2 mutant displayed a tendency toward a reduced ability to adhere to oral keratinocytes. Taken together, our results indicate an important role for c-di-AMP signaling in cellular processes important for colonization of the mouth.

• Kaspersen, Håkon; Fiskebeck, Eve Marie Louise Zeyl; Sekse, Camilla; Slettemeås, Jannice Schau; Urdahl, Anne Margrete & Norström, Madelaine [Show all 8 contributors for this article] (2020). Comparative genome analyses of wild type- and quinolone resistant Escherichia coli indicate dissemination of QREC in the Norwegian broiler breeding pyramid. Frontiers in Microbiology. doi: 10.3389/fmicb.2020.00938. Full text in Research Archive
• Kaspersen, Håkon; Sekse, Camilla; Fiskebeck, Eve Marie Louise Zeyl; Slettemeås, Jannice Schau; Simm, Roger & Norström, Madelaine [Show all 8 contributors for this article] (2020). Dissemination of Quinolone-Resistant Escherichia coli in the Norwegian Broiler and Pig Production Chains and Possible Persistence in the Broiler Production Environment. Applied and Environmental Microbiology. ISSN 0099-2240. doi: 10.1128/AEM.02769-19. Full text in Research Archive Show summary

  In Norway, the use of quinolones in livestock populations is very low, and prophylactic use is prohibited. Despite this, quinolone-resistant Escherichia coli (QREC) isolates are present at low levels in several animal species. The source of these QREC isolates is unknown. The aim of this study was to characterize and compare QREC isolates from different animal species to identify putative factors that may promote the occurrence of QREC. A total of 280 QREC isolates, from broilers, pigs, red foxes, and wild birds, were whole-genome sequenced and analyzed. Well-known chromosomal and plasmid-mediated resistance mechanisms were identified. In addition, mutations in marR, marA, and rpoB causing novel amino acid substitutions in their respective proteins were detected. Phylogenetic analyses were used to determine the relationships between the isolates. Quinolone resistance mechanism patterns appeared to follow sequence type groups. Similar QREC isolates with similar resistance mechanism patterns were detected from the samples, and further phylogenetic analysis indicated close evolutionary relationships between specific isolates from different sources. This suggests the dissemination of highly similar QREC isolates between animal species and also the persistence of QREC strains within the broiler production chain. This highlights the importance of both control measures at the top of the production chain as well as biosecurity measures to avoid the further dissemination and persistence of QREC in these environments.

• Vestby, Lene Karine; Grønseth, Torstein; Simm, Roger & Nesse, Live Lingaas (2020). Bacterial biofilm and its role in the pathogenesis of disease. Antibiotics. 9:59(2), p. 1–29. doi: 10.3390/antibiotics9020059. Full text in Research Archive Show summary

  Recognition of the fact that bacterial biofilm may play a role in the pathogenesis of disease has led to an increased focus on identifying diseases that may be biofilm-related. Biofilm infections are typically chronic in nature, as biofilm-residing bacteria can be resilient to both the immune system, antibiotics, and other treatments. This is a comprehensive review describing biofilm diseases in the auditory, the cardiovascular, the digestive, the integumentary, the reproductive, the respiratory, and the urinary system. In most cases reviewed, the biofilms were identified through various imaging technics, in addition to other study approaches. The current knowledge on how biofilm may contribute to the pathogenesis of disease indicates a number of different mechanisms. This spans from biofilm being a mere reservoir of pathogenic bacteria, to playing a more active role, e.g., by contributing to inflammation. Observations also indicate that biofilm does not exclusively occur extracellularly, but may also be formed inside living cells. Furthermore, the presence of biofilm may contribute to development of cancer. In conclusion, this review shows that biofilm is part of many, probably most chronic infections. This is important knowledge for development of effective treatment strategies for such infections.

• Naemi, Ali-Oddin; Dey, Hymonti; Kiran, Nosheen; Sandvik, Sarah Torbergsen; Slettemeås, Jannice Schau & Nesse, Live Lingaas [Show all 7 contributors for this article] (2020). NarAB Is an ABC-Type Transporter That Confers Resistance to the Polyether Ionophores Narasin, Salinomycin, and Maduramicin, but Not Monensin. Frontiers in Microbiology. 11:104, p. 1–9. doi: 10.3389/fmicb.2020.00104. Full text in Research Archive Show summary

  Polyether ionophores are antimicrobial compounds used as feed additives in poultry feed to control diseases caused by coccidia. In addition to the anticoccidial activity of these compounds, polyether ionophores also contain antibacterial properties. Resistance to the polyether ionophore narasin was recently shown to exist on mobile plasmids in Enterococcus faecium and the resistance mechanism was suggested to be associated with a two-gene operon encoding an ABC-type transporter. In this study we demonstrate that the genes encoding the putative narasin resistance mechanism confers reduced susceptibility to the polyether ionophores narasin, salinomycin and maduramicin, but not to monensin and suggest that this resistance mechanism should be referred to as NarAB. Importantly, NarAB does not affect the susceptibility of E. faecium to any of the tested antimicrobial compounds that are used in clinical medicine. However, we show that conjugation in the presence of certain polyether ionophores increases the number of vancomycin resistant E. faecium suggesting that narasin and certain other polyether ionophores can contribute to the persistence of VRE in poultry populations.

• Rørvik, Gro Herredsvela; Liskiewicz, Krystyna Anna; Kryuchkov, Fedor; Naemi, Ali-Oddin; aasheim, Hans-Christian & Petersen, Fernanda Cristina [Show all 8 contributors for this article] (2020). Cyclic di-adenosine monophosphate regulates metabolism and growth in the oral commensal streptococcus mitis. Microorganisms. 8:1269(9), p. 1–21. doi: 10.3390/microorganisms8091269. Full text in Research Archive Show summary

  Cyclic di-adenosine monophosphate (c-di-AMP) has emerged as an important bacterial signaling molecule that functions both as an intracellular second messenger in bacterial cells and an extracellular ligand involved in bacteria-host cross-talk. In this study, we identify and characterize proteins involved in controlling the c-di-AMP concentration in the oral commensal and opportunistic pathogen Streptococcusmitis (S. mitis). We identified three known types of c-di-AMP turnover proteins in the genome of S. mitis CCUG31611: a CdaA-type diadenylate cyclase as well as GdpP-, and DhhP-type phosphodiesterases. Biochemical analyses of purified proteins demonstrated that CdaA synthesizes c-di-AMP from ATP whereas both phosphodiesterases can utilize c-di-AMP as well as the intermediary metabolite of c-di-AMP hydrolysis 5′-phosphadenylyl-adenosine (pApA) as substrate to generate AMP, albeit at different catalytic efficiency. Using deletion mutants of each of the genes encoding c-di-AMP turnover proteins, we show by high resolution MS/MS that the intracellular concentration of c-di-AMP is increased in deletion mutants of the phosphodiesterases and non-detectable in the cdaA-mutant. We also detected pApA in mutants of the DhhP-type phosphodiesterase. Low and high levels of c-di-AMP were associated with longer and shorter chains of S. mitis, respectively indicating a role in regulation of cell division. The deletion mutant of the DhhP-type phosphodiesterase displayed slow growth and reduced rate of glucose metabolism.

• Enersen, Morten; Hultin, Margareta; Kønønen, Eija; Poulsen, Anne Havemose & Simm, Roger (2019). Antibiotics in the treatment of periodontal and peri-implant infections. Tandlægebladet. ISSN 0039-9353. 129(3), p. 224–235. Full text in Research Archive
• Simm, Roger; Slettemeås, Jannice Schau; Norström, Madelaine; Dean, Katharine Rose; Kaldhusdal, Magne & Urdahl, Anne Margrete (2019). Significant reduction of vancomycin resistant E. faecium in the Norwegian broiler population coincided with measures taken by the broiler industry to reduce antimicrobial resistant bacteria. PLOS ONE. 14(12). doi: 10.1371/journal.pone.0226101. Full text in Research Archive Show summary

  Vancomycin resistant enterococci (VRE) belong to the most common causes of nosocomial infections worldwide. It has been reported that use of the glycopeptide growth promoter avoparcin selected for a significant livestock-reservoir of VRE in many European countries, including Norway. However, although avoparcin was banned as a feed-additive in 1995, VRE have for unknown reasons consistently been reported in samples from Norwegian broilers. When avoparcin was banned, broiler-feed was supplemented with the polyether ionophore narasin in order to control the diseases coccidiosis and the frequent sequela necrotic enteritis. A potential link between transferrable vancomycin resistance and reduced susceptibility to narasin was recently reported. The use of narasin as a feed additive was abolished by the Norwegian broiler industry in 2016 and since then, broilers have been reared without in-feed antibacterial supplements. In this study, we demonstrate that all VRE isolates from Norwegian broilers collected in 2006–2014 displayed reduced susceptibility to narasin. Surveillance data collected two years after the narasin abolishment show a significant reduction in VRE, below the detection limit of the surveillance method, and a concurrent marked reduction in Enterococcus faecium with reduced susceptibility to narasin. The significant decline of E. faecium with reduced susceptibility to these antimicrobial compounds also coincided with an increased focus on cleaning and disinfection between broiler flocks. Furthermore, data from a controlled in vivo experiment using Ross 308 broilers indicate that the proportion of E. faecium with reduced susceptibility to narasin was heavily reduced in broilers fed a narasin-free diet compared to a diet supplemented with narasin. Our results are consistent with that the abolishment of this feed additive, possibly in combination with the increased focus on cleaning and disinfection, has had a substantial impact on the occurrence of VRE in the Norwegian broiler population.

• Paulsen, Britt; Fredriksen, Kim Alex; Petersen, Dirk; Maes, Louis; Matheeussen, An & Naemi, Ali-Oddin [Show all 12 contributors for this article] (2019). Synthesis and antimicrobial activities of N6-hydroxyagelasine analogs and revision of the structure of ageloximes. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 27(4), p. 620–629. doi: 10.1016/j.bmc.2019.01.002. Full text in Research Archive Show summary

  (+)-N6-Hydroxyagelasine D, the enantiomer of the proposed structure of (–)-ageloxime D, as well as N6-hydroxyagelasine analogs were synthesized by selective N-7 alkylation of N6-[tert-butyl(dimethyl)silyloxy]-9-methyl-9H-purin-6-amine in order to install the terpenoid side chain, followed by fluoride mediated removal of the TBDMS-protecting group. N6-Hydroxyagelasine D and the analog carrying a geranylgeranyl side chain displayed profound antimicrobial activities against several pathogenic bacteria and protozoa and inhibited bacterial biofilm formation. However these compounds were also toxic towards mammalian fibroblast cells (MRC-5). The spectral data of N6-hydroxyagelasine D did not match those reported for ageloxime D before. Hence, a revised structure of ageloxime D was proposed. Basic hydrolysis of agelasine D gave (+)-N-[4-amino-6-(methylamino)pyrimidin-5-yl]-N-copalylformamide, a compound with spectral data in full agreement with those reported for (–)-ageloxime D.

• Nesse, Live Lingaas & Simm, Roger (2018). Biofilm: A Hotspot for Emerging Bacterial Genotypes. Advances in Applied Microbiology. ISSN 0065-2164. 103, p. 223–246. doi: 10.1016/bs.aambs.2018.01.003. Full text in Research Archive Show summary

  Bacteria have the ability to adapt to changing environments through rapid evolution mediated by modification of existing genetic information, as well as by horizontal gene transfer (HGT). This makes bacteria a highly successful life form when it comes to survival. Unfortunately, this genetic plasticity may result in emergence and dissemination of antimicrobial resistance and virulence genes, and even the creation of multiresistant “superbugs” which may pose serious threats to public health. As bacteria commonly reside in biofilms, there has been an increased interest in studying these phenomena within biofilms in recent years. This review summarizes the present knowledge within this important area of research. Studies on bacterial evolution in biofilms have shown that mature biofilms develop into diverse communities over time. There is growing evidence that the biofilm lifestyle may be more mutagenic than planktonic growth. Furthermore, all three main mechanisms for HGT have been observed in biofilms. This has been shown to occur both within and between bacterial species, and higher transfer rates in biofilms than in planktonic cultures were detected. Of special concern are the observations that mutants with increased antibiotic resistance occur at higher frequency in biofilms than in planktonic cultures even in the absence of antibiotic exposure. Likewise, efficient dissemination of antimicrobial resistance genes, as well as virulence genes, has been observed within the biofilm environment. This new knowledge emphasizes the importance of biofilm awareness and control.

• Kaspersen, Håkon; Urdahl, Anne Margrete; Simm, Roger; Slettemeås, Jannice Schau; Lagesen, Karin & Norström, Madelaine (2018). Occurrence of quinolone resistant E. coli originating from different animal species in Norway. Veterinary Microbiology. ISSN 0378-1135. 217, p. 25–31. doi: 10.1016/j.vetmic.2018.02.022. Full text in Research Archive Show summary

  The aim of this study was to describe and compare the occurrence of quinolone resistant Escherichia coli (QREC) in various animal species in relation to human population density. Data from the Norwegian monitoring programme for antimicrobial resistance in feed, food and animals from 2006 to 2016 was compiled and analysed. In total, 4568 E. coli isolates were included in this study. The isolates originated from broilers, layers, cattle, turkeys, dogs, wild birds, red foxes, reindeer, sheep, horses and pigs. Data regarding the geographical location of sampling was obtained for 4050 of these isolates and used to categorize the isolates depending on the human population density of the area. In total, 1.4% of the isolates were categorized as quinolone resistant. Compared to most European countries, there was an overall low occurrence of QREC in various animal species in Norway, though with an interspecies variation with the highest occurrence in broilers and wild birds (p < 0.05). Human population density was not associated with the occurrence of QREC. Since fluoroquinolones are not used prophylactically and in almost negligent amounts in various species in Norway, the interspecies variation in the occurrence of QREC suggests that other factors than fluoroquinolone use may be important in the development of QREC.

• Hassan, Karl A.; Fagerlund, Annette; Elbourne, Liam D.H.; Vörös, Aniko; Kroeger, Jasmin Kaori & Simm, Roger [Show all 12 contributors for this article] (2017). The putative drug efflux systems of the Bacillus cereus group. PLOS ONE. 12(5), p. 1–25. doi: 10.1371/journal.pone.0176188. Full text in Research Archive Show summary

  The Bacillus cereus group of bacteria includes seven closely related species, three of which, B. anthracis, B. cereus and B. thuringiensis, are pathogens of humans, animals and/ or insects. Preliminary investigations into the transport capabilities of different bacterial lineages suggested that genes encoding putative efflux systems were unusually abundant in the B. cereus group compared to other bacteria. To explore the drug efflux potential of the B. cereus group all putative efflux systems were identified in the genomes of prototypical strains of B. cereus, B. anthracis and B. thuringiensis using our Transporter Automated Annotation Pipeline. More than 90 putative drug efflux systems were found within each of these strains, accounting for up to 2.7% of their protein coding potential. Comparative analyses demonstrated that the efflux systems are highly conserved between these species; 70± 80% of the putative efflux pumps were shared between all three strains studied. Furthermore, 82% of the putative efflux system proteins encoded by the prototypical B. cereus strain ATCC 14579 (type strain) were found to be conserved in at least 80% of 169 B. cereus group strains that have high quality genome sequences available. However, only a handful of these efflux pumps have been functionally characterized. Deletion of individual efflux pump genes from B. cereus typically had little impact to drug resistance phenotypes or the general fitness of the strains, possibly because of the large numbers of alternative efflux systems that may have overlapping substrate specificities. Therefore, to gain insight into the possible transport functions of efflux systems in B. cereus, we undertook large-scale qRTPCR analyses of efflux pump gene expression following drug shocks and other stress treatments. Clustering of gene expression changes identified several groups of similarly regulated systems that may have overlapping drug resistance functions. In this article we review current knowledge of the small molecule efflux pumps encoded by the B. cereus group and suggest the likely functions of numerous uncharacterised pumps.

• Simm, Roger; Kvalvaag, Audun Sverre Myrset; Deurs, Bo van; Lindback, Toril & Sandvig, Kirsten (2017). Benzyl alcohol induces a reversible fragmentation of the Golgi apparatus and inhibits membrane trafficking between endosomes and the trans-Golgi network. Experimental Cell Research. ISSN 0014-4827. 357(1), p. 67–78. doi: 10.1016/j.yexcr.2017.04.025. Full text in Research Archive
• Cimdins, Annika; Simm, Roger; Li, Fengyang; Lüthje, Petra; Thorell, Kaisa & Sjöling, Åsa [Show all 8 contributors for this article] (2017). Alterations of c-di-GMP turnover proteins modulate semi-constitutive rdar biofilm formation in commensal and uropathogenic Escherichia coli. MicrobiologyOpen. 6(5). doi: 10.1002/mbo3.508. Full text in Research Archive
• Kroeger, Jasmin Kaori; Hassan, Karl; Vörös, Aniko; Simm, Roger; Saidijam, Massoud & Bettaney, Kim E. [Show all 10 contributors for this article] (2015). Bacillus cereus efflux protein BC3310 - A multidrug transporter of the unknown major facilitator family, UMF-2. Frontiers in Microbiology. 6. doi: 10.3389/fmicb.2015.01063. Full text in Research Archive
• Guyon, Soazig Le; Simm, Roger; Rehn, Mikael & Römling, Ute (2015). Dissecting the cyclic di-guanylate monophosphate signalling network regulating motility in Salmonella enterica serovar Typhimurium. Environmental Microbiology. ISSN 1462-2912. 17(4), p. 1310–1320. doi: 10.1111/1462-2920.12580. Full text in Research Archive
• Kymre, Linn Furebotten; Simm, Roger; Skotland, Tore & Sandvig, Kirsten (2015). Different roles of the C-terminal end of Stx1A and Stx2A for AB5 complex integrity and retrograde transport of Stx in HeLa cells. Pathogens and Disease. 73(9), p. 1–9. doi: 10.1093/femspd/ftv083. Full text in Research Archive
• Kavaliauskiene, Simona; Skotland, Tore; Sylvänne, Tuulia; Simolin, Helena; Klokk, Tove Irene & Torgersen, Maria Lyngaas [Show all 10 contributors for this article] (2015). Novel actions of 2-deoxy-D-glucose: Protection against Shiga toxins and changes in cellular lipids. Biochemical Journal. ISSN 0264-6021. 470, p. 23–37. doi: 10.1042/BJ20141562. Full text in Research Archive
• Lingelem, Anne Berit Dyve; Hjelseth, Ieva Ailte; Simm, Roger; Torgersen, Maria Lyngaas & Sandvig, Kirsten (2015). Geldanamycin enhances retrograde transport of Shiga toxin in HEp-2 cells. PLOS ONE. 10:e0129214(5). doi: 10.1371/journal.pone.0129214. Full text in Research Archive
• Vörös, Aniko; Simm, Roger; Slamti, Leyla; McKay, Matthew J.; Hegna, Ida Kristin & Nielsen-Leroux, Christina [Show all 12 contributors for this article] (2014). SecDF as part of the sec-translocase facilitates efficient secretion of Bacillus cereus toxins and cell wall-associated proteins. PLOS ONE. 9:e0103326(8). doi: 10.1371/journal.pone.0103326. Full text in Research Archive
• Simm, Roger; Ahmad, Irfan; Rhen, Mikael; Guyon, Soazig Le & Römling, Ute (2014). Regulation of biofilm formation in Salmonella enterica serovar Typhimurium. Future Microbiology. ISSN 1746-0913. 9(11), p. 1261–1282. doi: 10.2217/fmb.14.88. Full text in Research Archive
• Bergan, Jonas; Skotland, Tore; Dyve, Lingelem Anne Berit; Simm, Roger; Spilsberg, Bjørn & Lindback, Toril [Show all 10 contributors for this article] (2014). The ether lipid precursor hexadecylglycerol protects against Shiga toxins. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 71, p. 4285–4300. doi: 10.1007/s00018-014-1624-1. Full text in Research Archive
• Kavaliauskiene, Simona; Nymark, Carl-Martin; Bergan, Jonas; Simm, Roger; Sylvänne, Tuulia & Simolin, Helena [Show all 9 contributors for this article] (2014). Cell density-induced changes in lipid composition and intracellular trafficking. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 71(6), p. 1097–1116. doi: 10.1007/s00018-013-1441-y. Full text in Research Archive
• Backe, Paul Hoff; Simm, Roger; Lærdahl, Jon Kristen; Dalhus, Bjørn; Fagerlund, Annette & Økstad, Ole Andreas Løchen [Show all 10 contributors for this article] (2013). A new family of proteins related to the HEAT-like repeat DNA glycosylases with affinity for branched DNA structures. Journal of Structural Biology. ISSN 1047-8477. 183(1), p. 66–75. doi: 10.1016/j.jsb.2013.04.007. Full text in Research Archive Show summary

  The recently discovered HEAT-like repeat (HLR) DNA glycosylase superfamily is widely distributed in all domains of life. The present bioinformatics and phylogenetic analysis shows that HLR DNA glycosylase superfamily members in the genus Bacillus form three subfamilies: AlkC, AlkD and AlkF/AlkG. The crystal structure of AlkF shows structural similarity with the DNA glycosylases AlkC and AlkD, however neither AlkF nor AlkG display any DNA glycosylase activity. Instead, both proteins have affinity to branched DNA structures such as three-way and Holliday junctions. A unique ß-hairpin in the AlkF/AlkG subfamily is most likely inserted into the DNA major groove, and could be a structural determinant regulating DNA substrate affinity. We conclude that AlkF and AlkG represent a new family of HLR proteins with affinity for branched DNA structures.

• Vörös, Aniko; Simm, Roger; Kroeger, Jasmin Kaori & Kolstø, Anne-Brit (2013). Gene transcription from the linear plasmid pBClin15 leads to cell lysis and extracellular DNA-dependent aggregation of Bacillus cereus ATCC 14579 in response to quinolone-induced stress. Microbiology (Reading). ISSN 1350-0872. 159, p. 2283–2293. doi: 10.1099/mic.0.069674-0. Full text in Research Archive
• Kvalvaag, Audun Sverre Myrset; Pust, Sascha; Sundet, Kristine Ingrid; Simm, Roger; Sandvig, Kirsten & Engedal, Kim Nikolai (2013). The ERM Proteins Ezrin and Moesin Regulate Retrograde Shiga Toxin Transport. Traffic: The moving front of cell biology. ISSN 1398-9219. 14(7), p. 839–852. doi: 10.1111/tra.12077. Full text in Research Archive
• Simm, Roger; Vörös, Aniko; Ekman, Jaakko V; Sødring, Marianne Sundt; Nes, Ingerid Veslemøy & Kroeger, Jasmin Kaori [Show all 11 contributors for this article] (2012). BC4707 Is a Major Facilitator Superfamily Multidrug Resistance Transport Protein from Bacillus cereus Implicated in Fluoroquinolone Tolerance. PLOS ONE. 7(5). doi: 10.1371/journal.pone.0036720. Full text in Research Archive
• Bergan, Jonas; Lingelem, Anne Berit Dyve; Simm, Roger; Skotland, Tore & Sandvig, Kirsten (2012). Shiga toxins. Toxicon. ISSN 0041-0101. 60(6), p. 1085–1107. doi: 10.1016/j.toxicon.2012.07.016. Full text in Research Archive

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• Dey, Hymonti; Simonovic, Danijela; Richard, Celine Sarah Marine; Hagen, Ingrid Sofie Norberg-Schultz; Johansen, Natascha & Øyen, Frode Jacobsen [Show all 11 contributors for this article] (2024). Combining outer membrane active synthetic antimicrobial peptides with vancomycin or erythromycin increases antibacterial and antibiofilm activities. Full text in Research Archive
• Simm, Roger (2023). C-di-AMP signaling regulates biofilm formation, stress tolerance and virulence in Streptococcus mitis. Full text in Research Archive
• Simm, Roger; Urdahl, Anne Margrete; Stassen, Joost & Pikkemaat, mariel (2023). Use of ionophores in poultry feed. The Veterinary Record. ISSN 0042-4900. doi: 10.1002/vetr.2710. Full text in Research Archive
• Frederiksen, Rikki Franklin; Lagesen, Karin; Simm, Roger; Granstad, Silje; Slettemeås, Jannice Schau & Urdahl, Anne Margrete (2023). Do polyether ionophore anticoccidials in feed drive selection of resistance to clinical antibiotics in enterococci from Norwegian poultry farms? Full text in Research Archive
• Hussain, Badra; Simm, Roger; Bueno, Jaime; Giannettou, Savvas; Naemi, Ali-Oddin & Lyngstadaas, Ståle Petter [Show all 7 contributors for this article] (2023). Chemical decontamination strategies for treatment of peri-implant disease. Full text in Research Archive
• Cai, Kun; Liskiewicz, Krystyna Anna; Sribasgaran, Biramitha; Naemi, Ali-Oddin & Simm, Roger (2023). The role of trkA and c-di-AMP in Streptococcus mitis. Full text in Research Archive
• Hussain, Badra; Simm, Roger; Lyngstadaas, Ståle Petter; Bueno, Jamie & Haugen, Håvard Jostein (2023). Chemical decontamination strategies for treatment of peri-implant disease: using an in vitro dental pellicle-, and a multispecies biofilm model. Full text in Research Archive
• Liskiewicz, Krystyna Anna; Araya, Feven Tesfaldet; Vallenari, Evan Michael; Parajuli, Himalaya; Ramstad, Silje & Schreurs, Olaf Joseph Franciscus [Show all 8 contributors for this article] (2023). Cyclic-di-adenosine monophosphate’s effect on virulence of Streptococcus mitis CCUG 31611. Full text in Research Archive
• Simm, Roger (2022). Ionophores – a One Health Issue? Full text in Research Archive
• Pikkemaat, mariel & Simm, Roger (2022). Ionophores – importance as a resistance driver, challenges and possible actions. Full text in Research Archive
• Paulsen, Britt; Fredriksen, Kim Alex; Petersen, Dirk; Maes, Louis; Matheeussen, An & Naemi, Ali-Oddin [Show all 12 contributors for this article] (2019). Synthesis directed towards bioactive ent-Ageloxime D and analogues. Full text in Research Archive
• Kaspersen, Håkon; Sekse, Camilla; Slettemeås, Jannice Schau; Simm, Roger; Norström, Madelaine & Urdahl, Anne Margrete [Show all 7 contributors for this article] (2019). Low-resolution MLST as an initial analysis for deep characterization of quinolone resistant Escherichia coli. Full text in Research Archive Show summary

  We are currently investigating the presence of putative antimicrobial resistance genes (ARG) and population structure in a set of quinolone resistant E. coli (QREC) from Norway, and as part of that study we are further investigating specific sequence types (ST). The goal of this study was to analyse clustering of isolates from selected STs, by utilizing whole genome MLST in addition to ARGs, virulence genes, and serotypes, to investigate the similarity between isolates from different animal species. A total of 285 QREC isolates originating from broilers, pigs, red foxes and wild birds were subjected to whole genome sequencing. ARGs were identified with ARIBA, with the MegaRes (intrinsic genes) and ResFinder (acquired genes) databases. Core genome multi locus sequence typing (cgMLST) with chewBBACA using the Enterobase scheme for E. coli was used for distance calculation and tree generation, and the regular sequence types (ST) were determined by the Escherichia coli #1 Enterobase scheme. STs which are represented with at least 10 isolates and that are present in at least three animal species was selected for serotyping, virulence gene identification and whole genome MLST (wgMLST) by using SeroTypeFinder, VirulenceFinder, and chewBBACA, respectively. Based on this, sequence types 10, 58, 155 and 162 were selected for further analyses. Some sequence types had a more homogenous distribution of ARGs than others. In regard to ARGs, serotypes, virulence genes and the wgMLST results, a higher diversity was seen in ST10 isolates. Serotypes clustered in concordance with wgMLST results, especially in ST162 and ST155.

• Paulsen, Britt; Fredriksen, Kim Alex; Petersen, Dirk; Maes, Louis; Matheeussen, An & Naemi, Ali-Oddin [Show all 11 contributors for this article] (2019). Synthesis directed towards bioactive ent-Ageloxime D and analogues. Full text in Research Archive
• Simm, Roger; Norström, Madelaine; Slettemeås, Jannice Schau & Urdahl, Anne Margrete (2019). No vancomycin resistant enterococci (VRE) detected in the Norwegian poultry Production for the first time since the monitoring started. In Simonsen, Gunnar Skov; Blix, Hege Salvesen; Grave, Kari & Urdahl, Anne Margrete (Ed.), NORM/NORM-VET 2018 Usage of Antimicrobial Agents and Occurrence of Antimicrobial Resistance in Norway. NORM/NORM-VET. Full text in Research Archive
• Liskiewicz, Krystyna Anna; Sunde, Pia Titterud; Verket, Anders; Økstad, Ole Andreas & Simm, Roger (2019). C-di-GMP signaling in Treponema denticola and its role in pathogenesis of periodontal diseases. Full text in Research Archive
• Liskiewicz, Krystyna Anna; Sunde, Pia Titterud; Verket, Anders; Økstad, Ole Andreas & Simm, Roger (2019). C-di-GMP signaling in Treponema denticola and its role in pathogenesis of periodontal diseases. Full text in Research Archive
• Simm, Roger (2019). Biofilms and antibiotic resistance: a curse of modern medicine. Full text in Research Archive
• Kaspersen, Håkon; Sekse, Camilla; Slettemeås, Jannice Schau; Simm, Roger; Norström, Madelaine & Sørum, Henning [Show all 8 contributors for this article] (2018). Quinolone resistance mechanisms in E. coli from four animal species in Norway. Full text in Research Archive
• Kaspersen, Håkon; Urdahl, Anne Margrete; Slettemeås, Jannice Schau; Simm, Roger; Sørum, Henning & Lagesen, Karin [Show all 7 contributors for this article] (2017). Quinolone resistance despite low antimicrobial usage: comparison of occurrence in different species in Norway the last ten years. Full text in Research Archive
• Vörös, Aniko; Simm, Roger; Schleimer, Jasmin Kaori; Tourasse, Nicolas; Henderson, Peter J. F. & Kolstø, Anne-Brit (2009). Functional characterization of putative multidrug resistance transporters conserved in the Bacillus cereus group. Full text in Research Archive
• Sandvig, Kirsten; Simm, Roger & Kymre, LInn (2014). Structure-function relationship of Shiga toxins; Role of the A-subunit in complex stability and endocytosis. Universitetet i Oslo. Full text in Research Archive

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