Kim Lewis

..Finally, one of the best bactericidal agents is rifampin, an inhibitor of RNA polymerase, and we suggest that it "kills" by preventing persister resuscitation...

..The function of these specialized dormant cells is to ensure the survival of the population in the presence of lethal factors...

..These sterile-surface materials kill both air- and waterborne pathogens and are not susceptible to existing resistance mechanisms...

..Persisters are essentially altruistic cells that forfeit propagation in order to ensure survival of kin cells in the presence of lethal factors...

..The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review...

..The data presented in this work raise intriguing questions about the nature of bacteria in many of the ancient samples reported to date: are they spores, persisters, sessile vegetative cells or do they make up a slow-growing population?..

..Other approaches to the problem include sterile-surface materials, prodrug antibiotics, and cyclical application of conventional antimicrobials...

..Can weakly active phytochemicals be combined synergistically to produce new antibacterial treatments?..

..Stress responses may act as general activators of persister formation. Proteins required for maintaining persisters may represent realistic targets for discovery of drugs capable of effectively treating chronic infections...

..The new cultivation approaches allow for the exploitation of the secondary metabolite potential of the previously inaccessible microorganisms...

..The hybrid molecule showed good efficacy in a Caenorhabditis elegans model of enterococcal infection, curing worms of the pathogen...

..elegans animals but do not affect the growth of the pathogen in vitro, thus acting by a mechanism of action distinct from antibiotics currently in clinical use...

..These findings show that induction of a classical resistance mechanism, MDR efflux, by oxidative stress leads to an increase in multidrug-tolerant persister cells...

..Recent progress in understanding persisters is encouraging, but the main obstacle in understanding their nature was our inability to isolate these elusive cells from a wild-type population since their discovery in 1944...

..This suggests that persisters are not at a particular stage in the cell cycle, neither are they defective cells nor cells created in response to antibiotics. Our data indicate that persisters are specialized survivor cells...

..Taken together, these results suggest that the protein kinase activity of HipA is essential for persister formation...

..Consistent with this scenario, the overexpression of both genes produced increased tolerance to ofloxacin...

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..Persisters may play a similarly critical role in the recalcitrance of other chronic infections...

..This unique survival mechanism may be an important factor influencing the outcome of antibiotic therapy in vivo...

..These results suggest that a DNA damage-induced toxin controls production of multidrug tolerant cells and thus provide a model of persister formation...

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..Among the repressed genes were those required for flagellar synthesis, energy metabolism, transport of small molecules, and protein synthesis...

..The screen was performed against C. albicans biofilms grown in microtitre plates in order to target the most resilient forms of the pathogen...

..Importantly, the trap cultivation resulted in the isolation of unusual and rare actinomycetes...

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..The drug tolerance of persisters may be a critical but overlooked component responsible for antimicrobial drug failure and relapsing infections...

..It remains to be seen whether attachment initiates dormancy that leads to the formation of fungal persisters. This study suggests that persisters may be largely responsible for the multidrug tolerance of fungal biofilms...

..Access to cultures of some of these species should be possible through identification of the signaling compounds necessary for growth, their addition to standard medium formulations, and eventual domestication...

..Our findings indicate that the whole-animal C. elegans screen identifies not only traditional antibiotics, but also compounds that target bacterial virulence or stimulate host defense...

..A mechanism-based evaluation of toxins based on real-time gene expression profiles promises, to be an efficient and informative method for toxicity assessment in environmental samples...

..This suggests that continuous cultivation in diffusion chambers adapts some microorganisms for growth under otherwise prohibitive in vitro conditions...

..A comparison of the persister transcriptome with transcriptomes obtained for several in vitro dormancy models identified a small number of genes upregulated in all cases, which may represent a core dormancy response...

..We further suggest that tolerance to antibiotics in stationary-phase or biofilm cultures is largely dependent on the presence of persister cells...

..From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis...

..These findings also suggest that plant antimicrobials might be developed into effective, broad-spectrum antibiotics in combination with inhibitors of MDRs...

..These isolates did not grow on artificial media alone but formed colonies in the presence of other microorganisms. This observation may help explain the nature of microbial uncultivability...

..The new method allows access to a large and diverse array of previously inaccessible microorganisms and is well suited for both fundamental and applied research...

..aureus overexpression and knockout isogenic efflux mutants for the NorA pump were done in order to assess whether the potentiating effects were associated with inhibition of this known pump mechanism...

..Finally, the immobilized N-alkyl-PEI, while deadly to bacteria, is determined to be harmless to mammalian (monkey kidney) cells...

..The compound [4-benzyloxy-2-(5-nitro-1H-2-yl)-phenyl]-methanol was the most potent pump inhibitor...

..The greatest loss of infectivity--up to a 4-log reduction in the titer--was observed with immobilized hydrophobic polyethylenimine-based and dendrimer-based polycations...

..aureus, but potentiated activity of the antibiotics berberine, rhein, ciprofloxacin and norfloxacin. Cellular concentrations of berberine were greatly increased in the presence of active esters...

..cereus. Compounds 4 and 7 were also found to potentiate the activity of berberine and of prescribed antibiotics, with 4 demonstrating a mode of action consistent with inhibition of the NorA MDR efflux pump in S. aureus...

..Thus, L. argenteus contains a weak antibacterial and also MDR pump inhibitors, which increase its potency...

..Various commercial synthetic polymers derivatized in this manner become bactericidal-they kill up to 99% of deposited, from either an aerosol or an aqueous suspension, Gram-positive and Gram-negative bacteria on contact...

..A promising new antibacterial lead compound against S. aureus (2-phenyl-1H-indol-5-yl)-methanol, was also found...

..Systematic chemical modifications of the immobilized PEI conducted herein shed light on the relationship between the structure of the polymer and the antibacterial efficiency of the resultant coating...

..The bactericidal textiles prepared herein are lethal not only to pathogenic bacteria but to fungi as well...

..aureus multidrug resistance (MDR) pump. These same two flavonols were earlier reported to potentiate the activity of artemisinin against Plasmodium falciparum...

..key personnel in alphabetical order, last name first; Name eRA Commons User Name Organization Role on Project Kim Lewis k.lewis@neu...

..Persisters are largely responsible for many serious relapsing infections. Identifying genes responsible for persister formation will lead to targets for developing an anti-persister therapy. ..

..We will develop an effective therapeutic against drug-resistant C. difficile by disabling the mechanism of resistance to berberine, a widely used antimicrobial from medicinal plants. ..

..Our findings are likely to change the way we view infectious diseases and will provide rational approaches for discovering drugs that completely eradicate the infection. ..

..Persisters are largely responsible for many serious relapsing infections. Identifying genes responsible for persister formation will lead to targets for developing an anti-persister therapy. ..

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..Our findings are likely to change the way we view infectious diseases and will provide rational approaches for discovering drugs that completely eradicate the infection. ..

..Unculturable bacteria are an enormous untapped source of potentially useful pharmaceutical compounds. Unculturable bacteria also make up most of the human oral and intestinal microflora. ..

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..MDR inhibitors will potentiate the action of conventional antibiotics, aiding eradication of multidrug resistant human pathogens. ..

..This information will likely contribute to the understanding of the mechanism of resistance. Resistance genes identified in this project will serve as targets for drug discovery and development of effective anti-biofilm therapies. ..

..Determination of chemical structure will be performed by a combination of MS and NMR methods. ..

..Determination of chemical structure will be performed by a combination of MS and NMR methods. ..

..These studies will form the basis for understanding biofilm infections and developing drugs that target persister proteins. ..

..We will also look for compounds that act specifically against the pathogen M. tuberculosis, which will avoid killing of the good bacteria of our gut flora. ..