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  • 1.
    Andersson, Emma K
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound2010In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, no 9, p. 3871-3877Article in journal (Refereed)
    Abstract [en]

    Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their anti-adenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential anti-adenoviral compounds. The assay is unique in that it is based on a replication competent adenovirus type 11p GFP-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by >/= 80% but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.

  • 2. Bengtsson-Palme, Johan
    et al.
    Angelin, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Huss, Mikael
    Kjellqvist, Sanela
    Kristiansson, Erik
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Larsson, D. G. Joakim
    Johansson, Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    The Human Gut Microbiome as a Transporter of Antibiotic Resistance Genes between Continents2015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 10, p. 6551-6560Article in journal (Refereed)
    Abstract [en]

    Previous studies of antibiotic resistance dissemination by travel have, by targeting only a select number of cultivable bacterial species, omitted most of the human microbiome. Here, we used explorative shotgun metagenomic sequencing to address the abundance of >300 antibiotic resistance genes in fecal specimens from 35 Swedish students taken before and after exchange programs on the Indian peninsula or in Central Africa. All specimens were additionally cultured for extended-spectrum beta-lactamase (ESBL)-producing enterobacteria, and the isolates obtained were genome sequenced. The overall taxonomic diversity and composition of the gut microbiome remained stable before and after travel, but there was an increasing abundance of Proteobacteria in 25/35 students. The relative abundance of antibiotic resistance genes increased, most prominently for genes encoding resistance to sulfonamide (2.6-fold increase), trimethoprim (7.7-fold), and beta-lactams (2.6-fold). Importantly, the increase observed occurred without any antibiotic intake. Of 18 students visiting the Indian peninsula, 12 acquired ESBL-producing Escherichia coli, while none returning from Africa were positive. Despite deep sequencing efforts, the sensitivity of metagenomics was not sufficient to detect acquisition of the low-abundant genes responsible for the observed ESBL phenotype. In conclusion, metagenomic sequencing of the intestinal microbiome of Swedish students returning from exchange programs in Central Africa or the Indian peninsula showed increased abundance of genes encoding resistance to widely used antibiotics.

  • 3. Charpentier, E
    et al.
    Courvalin, P
    Antibiotic resistance in Listeria spp.1999In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 43, no 9, p. 2103-2108Article in journal (Refereed)
  • 4. Charpentier, E
    et al.
    Courvalin, P
    Emergence of the trimethoprim resistance gene dfrD in Listeria monocytogenes BM4293.1997In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 41, no 5, p. 1134-1136Article in journal (Refereed)
    Abstract [en]

    The sequence of the trimethoprim resistance gene of the 3.7-kb plasmid (pIP823) that confers high-level resistance (MIC, 1,024 microg/ml) to Listeria monocytogenes BM4293 was determined. The gene was identical to dfrD recently detected in Staphylococcus haemolyticus MUR313. The corresponding protein, S2DHFR, represents the second class of high-level trimethoprim-resistant dihydrofolate reductase identified in gram-positive bacteria. We propose that trimethoprim resistance in L. monocytogenes BM4293 could originate in staphylococci.

  • 5. Charpentier, E
    et al.
    Gerbaud, G
    Courvalin, P
    Presence of the Listeria tetracycline resistance gene tet(S) in Enterococcus faecalis.1994In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 38, no 10, p. 2330-2335Article in journal (Refereed)
    Abstract [en]

    Two hundred thirty-eight tetracycline- and minocycline-resistant clinical isolates of Enterococcus and Streptococcus spp. were investigated by dot blot hybridization for the presence of nucleotide sequences related to tet(S) (first detected in Listeria monocytogenes BM4210), tet(K), tet(L), tet(M), tet(O), tet(P), and tet(Q) genes. The tet(S) determinant was found in 22 strains of Enterococcus faecalis, associated with tet(M) in 9 of these isolates and further associated with tet(L) in 3 of these strains. tet(M) was detected in all strains of Streptococcus spp. and in all but 10 isolates of Enterococcus spp.; tet(L) was found in 93 enterococci and tet(O) was found in single isolates of E. faecalis and Streptococcus milleri. No hybridization with the tet(K), tet(P), and tet(Q) probes was observed. Transfer of tet(S) by conjugation to E. faecalis or to E. faecalis and L. monocytogenes was obtained from 8 of the 10 E. faecalis strains harboring only this tet gene. Hybridization experiments with DNAs of four donors and of the corresponding transconjugants suggested that tet(S) was located in the chromosome. These results indicate that the genetic support of tet(S) in E. faecalis is different from that in L. monocytogenes, where it is carried by self-transferable plasmids, and confirm the notion of exchange of genetic information between Enterococcus and Listeria spp. in nature.

  • 6. Gillman, Anna
    et al.
    Nykvist, Marie
    Muradrasoli, Shaman
    Söderström, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wille, Michelle
    Daggfeldt, Annika
    Bröjer, Caroline
    Waldenström, Jonas
    Olsen, Björn
    Järhult, Josef D.
    Influenza A(H7N9) Virus Acquires Resistance-Related Neuraminidase I222T Substitution When Infected Mallards Are Exposed to Low Levels of Oseltamivir in Water2015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 9, p. 5196-5202Article in journal (Refereed)
    Abstract [en]

    Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and new human IAVs often contain gene segments originating from avian IAVs. Treatment options for severe human influenza are principally restricted to neuraminidase inhibitors (NAIs), among which oseltamivir is stockpiled in preparedness for influenza pandemics. There is evolutionary pressure in the environment for resistance development to oseltamivir in avian IAVs, as the active metabolite oseltamivir carboxylate (OC) passes largely undegraded through sewage treatment to river water where waterfowl reside. In an in vivo mallard (Anas platyrhynchos) model, we tested if low-pathogenic avian influenza A(H7N9) virus might become resistant if the host was exposed to low levels of OC. Ducks were experimentally infected, and OC was added to their water, after which infection and transmission were maintained by successive introductions of uninfected birds. Daily fecal samples were tested for IAV excretion, genotype, and phenotype. Following mallard exposure to 2.5 μg/liter OC, the resistance-related neuraminidase (NA) I222T substitution, was detected within 2 days during the first passage and was found in all viruses sequenced from subsequently introduced ducks. The substitution generated 8-fold and 2.4-fold increases in the 50% inhibitory concentration (IC50) for OC (P < 0.001) and zanamivir (P = 0.016), respectively. We conclude that OC exposure of IAV hosts, in the same concentration magnitude as found in the environment, may result in amino acid substitutions, leading to changed antiviral sensitivity in an IAV subtype that can be highly pathogenic to humans. Prudent use of oseltamivir and resistance surveillance of IAVs in wild birds are warranted.

  • 7.
    Karah, Nabil
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Dwibedi, Chinmay Kumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöström, Karin
    Edquist, Petra
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Novel Aminoglycoside Resistance Transposons and Transposon-Derived Circular Forms Detected in Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates2016In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 60, no 3, p. 1801-1818Article in journal (Refereed)
    Abstract [en]

    Acinetobacter baumannii has emerged as an important opportunistic pathogen equipped with a growing number of antibiotic resistance genes. Our study investigated the molecular epidemiology and antibiotic resistance features of 28 consecutive carbapenem-resistant clinical isolates of A. baumannii collected throughout Sweden in 2012 and 2013. The isolates mainly belonged to clonal complexes (CCs) with an extensive international distribution, such as CC2 (n = 16) and CC25 (n = 7). Resistance to carbapenems was related to bla(OXA-23) (20 isolates), bla(OXA-24/40-like) (6 isolates), bla(OXA-467) (1 isolate), and ISAba1-bla(OXA-69) (1 isolate). Ceftazidime resistance was associated with bla(PER-7) in the CC25 isolates. Two classical point mutations were responsible for resistance to quinolones in all the isolates. Isolates with high levels of resistance to aminoglycosides carried the 16S rRNA methylase armA gene. The isolates also carried a variety of genes encoding aminoglycoside-modifying enzymes. Several novel structures involved in aminoglycoside resistance were identified, including Tn6279, Delta Tn6279, Ab-ST3- aadB, and different assemblies of Tn6020 and TnaphA6. Importantly, a number of circular forms related to the IS26 or ISAba125 composite trans-posons were detected. The frequent occurrence of these circular forms in the populations of several isolates indicates a potential role of these circular forms in the dissemination of antibiotic resistance genes.

  • 8. Kudrin, Pavel
    et al.
    Varik, Vallo
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Tartu, Estonia.
    Oliveira, Sofia Raquel Alves
    Beljantseva, Jelena
    Santos, Teresa Del Peso
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Dzhygyr, Ievgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rejman, Dominik
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Tenson, Tanel
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Tartu, Estonia.
    Subinhibitory Concentrations of Bacteriostatic Antibiotics Induce relA-Dependent and relA-Independent Tolerance to beta-Lactams2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 4, article id e02173-16Article in journal (Refereed)
    Abstract [en]

    The nucleotide (p) ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance, and virulence. During amino acid starvation, the Escherichia coli (p) ppGpp synthetase RelA is activated by deacylated tRNA in the ribosomal A-site. An increase in (p) ppGpp is believed to drive the formation of antibiotic-tolerant persister cells, prompting the development of strategies to inhibit (p) ppGpp synthesis. We show that in a biochemical system from purified E. coli components, the antibiotic thiostrepton efficiently inhibits RelA activation by the A-site tRNA. In bacterial cultures, the ribosomal inhibitors thiostrepton, chloramphenicol, and tetracycline all efficiently abolish accumulation of (p) ppGpp induced by the Ile-tRNA synthetase inhibitor mupirocin. This abolishment, however, does not reduce the persister level. In contrast, the combination of dihydrofolate reductase inhibitor trimethoprim with mupirocin, tetracycline, or chloramphenicol leads to ampicillin tolerance. The effect is independent of RelA functionality, specific to beta-lactams, and not observed with the fluoroquinolone norfloxacin. These results refine our understanding of (p) ppGpp's role in antibiotic tolerance and persistence and demonstrate unexpected drug interactions that lead to tolerance to bactericidal antibiotics.

  • 9.
    Lindgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gallium Potentiates the Antibacterial Effect of Gentamicin against Francisella tularensis2016In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 60, no 1, p. 288-295Article in journal (Refereed)
    Abstract [en]

    The reasons why aminoglycosides are bactericidal have not been not fully elucidated, and evidence indicates that the cidal effects are at least partly dependent on iron. We demonstrate that availability of iron markedly affects the susceptibility of the facultative intracellular bacterium Francisella tularensis strain SCHU S4 to the aminoglycoside gentamicin. Specifically, the intracellular depots of iron were inversely correlated to gentamicin susceptibility, whereas the extracellular iron concentrations were directly correlated to the susceptibility. Further proof of the intimate link between iron availability and antibiotic susceptibility were the findings that a Delta fslA mutant, which is defective for siderophore-dependent uptake of ferric iron, showed enhanced gentamicin susceptibility and that a Delta feoB mutant, which is defective for uptake of ferrous iron, displayed complete growth arrest in the presence of gentamicin. Based on the aforementioned findings, it was hypothesized that gallium could potentiate the effect of gentamicin, since gallium is sequestered by iron uptake systems. The ferrozine assay demonstrated that the presence of gallium inhibited >70% of the iron uptake. Addition of gentamicin and/or gallium to infected bone marrow-derived macrophages showed that both 100 mu M gallium and 10 mu g/ml of gentamicin inhibited intracellular growth of SCHU S4 and that the combined treatment acted synergistically. Moreover, treatment of F. tularensis-infected mice with gentamicin and gallium showed an additive effect. Collectively, the data demonstrate that SCHU S4 is dependent on iron to minimize the effects of gentamicin and that gallium, by inhibiting the iron uptake, potentiates the bactericidal effect of gentamicin in vitro and in vivo.

  • 10.
    Marwaha, Sania
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Salin, Olli
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 5, p. 2968-2971Article in journal (Refereed)
    Abstract [en]

    Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.

  • 11.
    Mojica, Sergio A.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Salin, Olli
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bastidas, Robert J.
    Sunduru, Naresh
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Núñez-Otero, Carlos
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Valdivia, Raphael H.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 10, article id e00716-17Article in journal (Refereed)
    Abstract [en]

    The type II fatty acid synthesis (FASII) pathway is essential for bacterial lipid biosynthesis and continues to be a promising target for novel antibacterial compounds. Recently, it has been demonstrated that Chlamydia is capable of FASII and this pathway is indispensable for Chlamydia growth. Previously, a high-content screen with Chlamydia trachomatis-infected cells was performed, and acylated sulfonamides were identified to be potent growth inhibitors of the bacteria. C. trachomatis strains resistant to acylated sulfonamides were isolated by serial passage of a wild-type strain in the presence of low compound concentrations. Results from whole-genome sequencing of 10 isolates from two independent drug-resistant populations revealed that mutations that accumulated in fabF were predominant. Studies of the interaction between the FabF protein and small molecules showed that acylated sulfonamides directly bind to recombinant FabF in vitro and treatment of C. trachomatis-infected HeLa cells with the compounds leads to a decrease in the synthesis of Chlamydia fatty acids. This work demonstrates the importance of FASII for Chlamydia development and may lead to the development of new antimicrobials.

  • 12. Osterblad, Monica
    et al.
    Karah, Nabil
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Halkilahti, Jani
    Sarkkinen, Hannu
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Jalava, Jari
    Rare Detection of the Acinetobacter Class D Carbapenemase bla(OXA-23) Gene in Proteus mirabilis2016In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 60, no 5, p. 3243-3245Article in journal (Refereed)
  • 13.
    Ranjbarian, Farahnaz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Alzahrani, Khalid J. H.
    Ebiloma, Godwin U.
    de Koning, Harry P.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 6, article id e02719-16Article in journal (Refereed)
    Abstract [en]

    Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasite Trypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cure T. brucei-infected mice, but they have the limitation of mainly being taken up by the P2 nucleoside transporter, which, when mutated, is a common cause of multidrug resistance in T. brucei. We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Like Ara-A, FANA-A was found to be resistant to cleavage by methylthioadenosine phosphorylase, an enzyme that protects T. brucei against the antitrypanosomal effects of deoxyadenosine. Another important factor behind the selectivity of nucleoside analogues is how well they are phosphorylated within the cell. We found that the T. brucei adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and T. brucei cells treated with FANA-A accumulated high levels of FANA-A triphosphate, which even surpassed the level of ATP and led to cell cycle arrest, inhibition of DNA synthesis, and the accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with 50% effective concentrations (EC(50)s) in the low nanomolar range, whereas mammalian cell proliferation was inhibited in the micromolar range. Both Ara-A and FANA-A, in combination with deoxycoformycin, cured T. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.

  • 14.
    Rzhepishevska, Olena
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekstrand-Hammarström, Barbro
    Swedish Defence Research Institute (FOI), Umeå, Sweden .
    Popp, Maximilian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Björn, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bucht, Anders
    Swedish Defence Research Institute (FOI), Umeå, Sweden .
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ramstedt, Madeleine
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The antibacterial activity of Ga3+ is influenced by Llgand complexation as well as the bacterial carbon source2011In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 55, no 12, p. 5568-5580Article in journal (Refereed)
    Abstract [en]

    Gallium ions have previously been shown to exhibit antibacterial and antibiofilm properties. In this study we report differential bactericidal activity of two gallium complexes; gallium desferrioxamine B (Ga-DFOB) and gallium citrate (Ga-cit). Modeling of gallium speciation in growth medium showed that DFOB and citrate both can prevent precipitation of Ga(OH)(3), but some precipitation can occur above pH 7 with citrate. Despite this, Ga-cit inhibitory concentrations (IC(90)) were lower than those of Ga-DFOB for clinical isolates of Pseudomonas aeruginosa, and several reference strains of other bacterial species. Treatment with Ga compounds mitigated damage inflicted on murine J774 macrophage-like cells infected with P. aeruginosa PAO1. Again, Ga-cit showed more potent mitigation than did Ga-DFOB. Ga was also taken up more efficiently by P. aeruginosa in the form of Ga-cit than in the form of Ga-DFOB. Neither Ga-cit nor Ga-DFOB was toxic to several human cell lines tested and no pro-inflammatory activity was detected in human lung epithelial cells after exposure in vitro. Metabolomic analysis was used to delineate the effects of Ga-cit on the bacterial cell. Exposure to Ga resulted in lower concentrations of glutamate, a key metabolite for P. aeruginosa, and of many amino acids, indicating that Ga affects various biosynthesis pathways. Altered protein expression profile in presence of Ga-cit suggested that some compensatory mechanisms were activated in the bacterium. Furthermore, the antibacterial effect of Ga was shown to vary depending on the carbon source, which has importance in the context of medical applications of gallium.

  • 15.
    Strand, Mårten
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Islam, Koushikul
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Öberg, Christopher T
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergström, Tomas
    Univ Gothenburg, Sahlgrenska Acad, Dept Virol, Gothenburg, Sweden.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 22012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 11, p. 5735-5743Article in journal (Refereed)
    Abstract [en]

    Herpes simplex viruses (HSV-1 and HSV-2) are responsible for life-long latent infections in humans, with periods of viral reactivation associated with recurring ulcerations in the orofacial and genital tract. In immunosuppressed patients and neonates, HSV infections are associated with severe morbidity, and in some cases even mortality. Today, acyclovir is the standard therapy for management of HSV infections. However, the need for novel antiviral agents is apparent since HSV isolates resistant to acyclovir therapy are frequently isolated in immunosuppressed patients. In this study, we assessed the anti-HSV activity of the anti-adenoviral compounds 2-[2-(2-benzoylamino)-benzoylamino]benzoic acid, (Benzavir-1) and 2-[4,5-difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, (Benzavir-2) on HSV-1 and HSV-2. Both compounds were active against both viruses. Importantly, Benzavir-2 had similar potency to acyclovir against both HSV types and it was active against clinical acyclovir-resistant HSV isolates.

  • 16.
    Stylianou, Marios
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kulesskiy, Evgeny
    Lopes, José Pedro
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Granlund, Margareta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Wennerberg, Krister
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Antifungal Application of Nonantifungal Drugs2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 2, p. 1055-1062Article in journal (Refereed)
    Abstract [en]

    Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to similar to 150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.

  • 17.
    Sun, Kun
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bröms, Jeanette
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gurram, Bharat Kumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Screening for inhibition of Vibrio cholerae VipA-VipB interaction identifies small-molecule compounds active against type VI secretion2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 7, p. 4123-4130Article in journal (Refereed)
    Abstract [en]

    The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an alpha-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A(1) activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance.

  • 18. Sundqvist, Martin
    et al.
    Granholm, Susanne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Naseer, Umaer
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Brolund, Alma
    Sundsfjord, Arnfinn
    Kahlmeter, Gunnar
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Within-population distribution of trimethoprim resistance in Escherichia coli before and after a community-wide intervention on trimethoprim use2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 12, p. 7492-7500Article in journal (Refereed)
    Abstract [en]

    A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a health care region with 178,000 inhabitants. Here, we performed before-and-after analyses of the within-population distribution of trimethoprim resistance in Escherichia coli. Phylogenetic and population genetic methods were applied to multilocus sequence typing data of 548 consecutively collected E. coli isolates from clinical urinary specimens. Results were analyzed in relation to antibiotic susceptibility and the presence and genomic location of different trimethoprim resistance gene classes. A total of 163 E. coli sequence types (STs) were identified, of which 68 were previously undescribed. The isolates fell into one of three distinct genetic clusters designated BAPS 1 (E. coli phylogroup B2), BAPS 2 (phylogroup A and B1), and BAPS 3 (phylogroup D), each with a similar frequency before and after the intervention. BAPS 2 and BAPS 3 were positively and BAPS 1 was negatively associated with trimethoprim resistance (odds ratios of 1.97, 3.17, and 0.26, respectively). In before-and-after analyses, trimethoprim resistance frequency increased in BAPS 1 and decreased in BAPS 2. Resistance to antibiotics other than trimethoprim increased in BAPS 2. Analysis of the genomic location of different trimethoprim resistance genes in isolates of ST69, ST58, and ST73 identified multiple independent acquisition events in isolates of the same ST. The results show that despite a stable overall resistance frequency in E. coli before and after the intervention, marked within-population changes occurred. A decrease of resistance in one major genetic cluster was masked by a reciprocal increase in another major cluster.

  • 19.
    Westman, Eva
    et al.
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Lundin, S
    Hermansson, A
    Melhus, Å
    Betalactamase-producing nontypeable Haemophilus influenzae fails to protect Streptococcus pneumoniae from Amoxicillin during experimental Acute Otitis Media2004In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 48, no 9, p. 3536-3542Article in journal (Refereed)
1 - 19 of 19
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