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  • 1.
    Andersson, Dan I
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nicoloff, Hervé
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechanisms and clinical relevance of bacterial heteroresistance2019In: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 17, no 8, p. 479-496Article, review/survey (Refereed)
    Abstract [en]

    Antibiotic heteroresistance is a phenotype in which a bacterial isolate contains subpopulations of cells that show a substantial reduction in antibiotic susceptibility compared with the main population. Recent work indicates that heteroresistance is very common for several different bacterial species and antibiotic classes. The resistance phenotype is often unstable, and in the absence of antibiotic pressure it rapidly reverts to susceptibility. A common mechanistic explanation for the instability is the occurrence of genetically unstable tandem amplifications of genes that cause resistance. Due to their instability, low frequency and transient character, it is challenging to detect and study these subpopulations, which often leads to difficulties in unambiguously classifying bacteria as susceptible or resistant. Finally, in vitro experiments, mathematical modelling, animal infection models and clinical studies show that the resistant subpopulations can be enriched during antibiotic exposure, and increasing evidence suggests that heteroresistance can lead to treatment failure.

  • 2.
    Nicoloff, Herve
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Indirect resistance to several classes of antibiotics in cocultures with resistant bacteria expressing antibiotic-modifying or -degrading enzymes2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 1, p. 100-110Article in journal (Refereed)
    Abstract [en]

    Objectives: The detection of indirect resistance in vitro suggests that coinfecting bacteria from the normal microbial flora may have a more important negative impact during antimicrobial therapy than is generally appreciated.Indirect resistance (IR), the ability of an antibiotic-resistant population of bacteria to protect a susceptible population, has been previously observed for beta-lactamase-producing bacteria and associated with antimicrobial treatment failures. Here, we determined whether other resistance determinants could cause IR in the presence of five other classes of antibiotics. Methods: A test was designed to detect IR and 14 antibiotic resistance genes were tested in the presence of 13 antibiotics from six classes. A bioassay was used to measure the ability of resistance-causing enzymes to decrease the concentration of active antibiotics in the medium. Results: We confirmed IR in the presence of beta-lactam antibiotics (ampicillin and mecillinam) when TEM-1A was expressed. We found that bacteria expressing antibiotic-modifying or -degrading enzymes Ere(A), Tet(X2) or CatA1 caused IR in the presence of macrolides (erythromycin and clarithromycin), tetracyclines (tetracycline and tigecycline) and chloramphenicol, respectively. IR was not observed with resistance determinants that did not modify or destroy antibiotics or with enzymes modifying aminoglycosides or degrading fosfomycin. IR was dependent on the resistance enzymes decreasing the concentration of active antibiotics in the medium, hence allowing nearby susceptible bacteria to resume growth once the antibiotic concentration fell below their MIC. Conclusions: IR was not limited to beta-lactamase-producing bacteria, but was also caused by resistant bacteria carrying cytoplasmic antibiotic-modifying or -degrading enzymes that catalyse energy-consuming reactions requiring complex cellular cofactors. Our results suggest that IR is common and further emphasizes that coinfecting agents and the human microflora can have a negative impact during antimicrobial therapy.

  • 3.
    Nicoloff, Hervé
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lon protease inactivation, or translocation of the lon gene, potentiate bacterial evolution to antibiotic resistance2013In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 90, no 6, p. 1233-1248Article in journal (Refereed)
    Abstract [en]

    Previous work demonstrated that selection for Escherichia coli mutants with low antibiotic resistance frequently resulted in co-selection of lon mutations and that lon(-) mutants evolved higher-level resistance faster than a lon(+) strain. Here we show that lon mutation causes a very low multidrug resistance by inducing the AcrAB-TolC pump via stabilization of the acrAB transcriptional activators MarA and SoxS, which are substrates of the Lon protease. Fast evolution of lon(-) mutants towards higher resistance involves selection of frequent next-step mutations consisting of large duplications including acrAB and the mutated lon gene. Resistance results from the combined effects of acrAB duplication and lon mutation increasing dosage of efflux pump. In contrast, when acrAB duplication occurs as the first step mutation, increased Lon activity caused by lon(+) co-duplication mitigates the effect of acrAB duplication on resistance, and faster evolution towards higher resistance is not observed. As predicted, when the functional lon gene is relocated far from acrAB to prevent their co-duplication, first-step acrAB duplication confers higher resistance, which then allows selection of frequent next-step mutations and results in faster evolution towards higher resistance. Our results demonstrate how order of appearance of mutations and gene location can influence the rate of resistance evolution.

  • 4.
    Nicoloff, Hervé
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA.
    Gopalkrishnan, Saumya
    Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA.;Univ Wisconsin Madison, Dept Bacteriol, Madison, WI USA..
    Ades, Sarah E.
    Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA..
    Appropriate Regulation of the sigma(E)-Dependent Envelope Stress Response Is Necessary To Maintain Cell Envelope Integrity and Stationary-Phase Survival in Escherichia coli2017In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 199, no 12, article id e00089Article in journal (Refereed)
    Abstract [en]

    The alternative sigma factor sigma(E) is a key component of the Escherichia coli response to cell envelope stress and is required for viability even in the absence of stress. The activity of sigma(E) increases during entry into stationary phase, suggesting an important role for sigma(E) when nutrients are limiting. Elevated sigma(E) activity has been proposed to activate a pathway leading to the lysis of nonculturable cells that accumulate during early stationary phase. To better understand sigma(E)-directed cell lysis and the role of sigma(E) in stationary phase, we investigated the effects of elevated sigma(E) activity in cultures grown for 10 days. We demonstrate that high sigma(E) activity is lethal for all cells in stationary phase, not only those that are nonculturable. Spontaneous mutants with reduced sigma(E) activity, due primarily to point mutations in the region of sigma(E) that binds the -35 promoter motif, arise and take over cultures within 5 to 6 days after entry into stationary phase. High sigma(E) activity leads to large reductions in the levels of outer membrane porins and increased membrane permeability, indicating membrane defects. These defects can be counteracted and stationary-phase lethality delayed significantly by stabilizing membranes with Mg2+ and buffering the growth medium or by deleting the sigma(E)-dependent small RNAs (sRNAs) MicA, RybB, and MicL, which inhibit the expression of porins and Lpp. Expression of these sRNAs also reverses the loss of viability following depletion of sigma E activity. Our results demonstrate that appropriate regulation of sigma(E) activity, ensuring that it is neither too high nor too low, is critical for envelope integrity and cell viability. IMPORTANCE The Gram-negative cell envelope and cytoplasm differ significantly, and separate responses have evolved to combat stress in each compartment. An array of cell envelope stress responses exist, each of which is focused on different parts of the envelope. The sigma(E) response is conserved in many enterobacteria and is tuned to monitor pathways for the maturation and delivery of outer membrane porins, lipoproteins, and lipopolysaccharide to the outer membrane. The activity of sigma(E) is tightly regulated to match the production of sigma(E) regulon members to the needs of the cell. In E. coli, loss of rho(E) results in lethality. Here we demonstrate that excessive sigma(E) activity is also lethal and results in decreased membrane integrity, the very phenotype the system is designed to prevent.

  • 5.
    Nicoloff, Hervé
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Levin, Bruce R.
    Emory Univ, Dept Biol, Atlanta, GA 30322 USA.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification2019In: Nature Microbiology, E-ISSN 2058-5276, Vol. 4, no 3, p. 504-514Article in journal (Refereed)
    Abstract [en]

    When choosing antibiotics to treat bacterial infections, it is assumed that the susceptibility of the target bacteria to an antibiotic is reflected by laboratory estimates of the minimum inhibitory concentration (MIC) needed to prevent bacterial growth. A caveat of using MIC data for this purpose is heteroresistance, the presence of a resistant subpopulation in a main population of susceptible cells. We investigated the prevalence and mechanisms of heteroresistance in 41 clinical isolates of the pathogens Escherichia coli, Salmonella enterica, Klebsiella pneumoniae and Acinetobacter baumannii against 28 different antibiotics. For the 766 bacteria-antibiotic combinations tested, as much as 27.4% of the total was heteroresistant. Genetic analysis demonstrated that a majority of heteroresistance cases were unstable, with an increased resistance of the subpopulations resulting from spontaneous tandem amplifications, typically including known resistance genes. Using mathematical modelling, we show how heteroresistance in the parameter range estimated in this study can result in the failure of antibiotic treatment of infections with bacteria that are classified as antibiotic susceptible. The high prevalence of heteroresistance with the potential for treatment failure highlights the limitations of MIC as the sole criterion for susceptibility determinations. These results call for the development of facile and rapid protocols to identify heteroresistance in pathogens.

  • 6.
    Olivenza, David R.
    et al.
    Univ Seville, Fac Biol, Dept Genet, Apartado 1095, E-41080 Seville, Spain.
    Nicoloff, Hervé
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antonia Sanchez-Romero, Maria
    Univ Seville, Fac Biol, Dept Genet, Apartado 1095, E-41080 Seville, Spain.
    Cota, Ignacio
    Univ Seville, Fac Biol, Dept Genet, Apartado 1095, E-41080 Seville, Spain;UB, UAB, IRTA, Ctr Res Agr Genom,CSIC, Campus UAB, Barcelona 08193, Spain.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Casadesus, Josep
    Univ Seville, Fac Biol, Dept Genet, Apartado 1095, E-41080 Seville, Spain.
    A portable epigenetic switch for bistable gene expression in bacteria2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 11261Article in journal (Refereed)
    Abstract [en]

    We describe a portable epigenetic switch based on opvAB, a Salmonella enterica operon that undergoes bistable expression under DNA methylation control. A DNA fragment containing the opvAB promoter and the opvAB upstream regulatory region confers bistability to heterologous genes, yielding OFF and ON subpopulations. Bistable expression under opvAB control is reproducible in Escherichia coli, showing that the opvAB switch can be functional in a heterologous host. Subpopulations of different sizes can be produced at will using engineered opvAB variants. Controlled formation of antibiotic-resistant and antibiotic-susceptible subpopulations may allow use of the opvAB switch in the study of bacterial heteroresistance to antibiotics.

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