Pseudomonas aeruginosa strain:ATCC 27853
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ABSTRACT:
PROVIDER: PRJNA316664 | ENA |
REPOSITORIES: ENA
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Project description:Pseudomonas aeruginosa is a leading cause of hospital acquired infections for which the development of new antibiotics is urgently needed. Unlike most enteric bacteria, P. aeruginosa lacks thymidine kinase and thymidine phosphorylase activity, and thus cannot scavenge exogenous thymine. An appealing strategy to selectively target P. aeruginosa while leaving the healthy microbiome largely intact would thus be to disrupt thymidine synthesis while providing exogenous thymine. However, this approach was previously intractable because known antibiotics that perturb thymidine synthesis are largely inactive against P. aeruginosa. Here, we characterize a novel dihydrofolate reductase inhibitor, fluorofolin, that exhibits significant activity against P. aeruginosa in culture and in a mouse thigh infection model. Fluorofolin is active against a wide range of clinical P. aeruginosa isolates resistant to known antibiotics, including critical antibiotic development priorities expressing the beta-lactamases KPC-5 and NDM-1. Importantly, in the presence of thymine supplementation, fluorofolin activity is selective for P. aeruginosa. Resistance to fluorofolin can emerge through overexpression of the efflux pumps MexCD-OprJ and MexEF-OprN. However, these mutants also decrease pathogenesis, in part due to increased export of quorum sensing precursors leading to decreased virulence factor production. Our findings thus demonstrate how understanding species-specific genetic differences and discovery of an antibiotic with a widely conserved target can enable selective targeting of important pathogens while revealing new tradeoffs between resistance and pathogenesis.
2024-02-07 | GSE249862 | GEO
Project description:Biofilms are ubiquitous in natural, medical, and engineering environments. While most antibiotics that primarily aim to inhibit cell growth may result in bacterial drug resistance, biofilm inhibitors do not affect cell growth and there is less chance of developing resistance. This work sought to identify novel, non-toxic and potent biofilm inhibitors from Streptomyces bacteria for reducing the biofilm formation of Pseudomonas aeruginosa PAO1. Out of 4300 Streptomyces strains, one species produced and secreted peptide(s) to inhibit P. aeruginosa biofilm formation by 93% without affecting the growth of planktonic cells. Global transcriptome analyses (DNA microarray) revealed that the supernatant of the Streptomyces 230 strain induced phenazine, pyoverdine, and pyochelin synthesis genes. Electron microscopy showed that the supernatant of Streptomyces 230 strain reduced the production of polymeric matrix in P. aeruginosa biofilm cells, while the Streptomyces species enhanced swarming motility of P. aeruginosa. Therefore, current study suggests that Streptomyces bacteria are an important resource of biofilm inhibitors as well as antibiotics.
2013-03-21 | GSE28194 | GEO
Project description:An antivirulence approach targets bacterial virulence rather than cell viability in the antibiotic approach that can readily lead to drug resistance. Opportunistic human pathogen Pseudomonas aeruginosa produces a variety of virulence factors, and biofilm cells of this bacterium are much more resistant to antibiotics than planktonic cells. To identify novel inorganic antivirulence compounds, the dual screenings of thirty-six metal ions were performed to identify that zinc ions and ZnO nanoparticle inhibited the pyocyanin production and biofilm formation in P. aeruginosa without affecting the growth of planktonic cells. Moreover, zinc ion and ZnO nanoparticle markedly reduced the production of 2-heptyl-3-hydroxy-4(1H)-quinolone and siderophore pyochelin, while increased the production of another sideropore pyoverdine and swarming motility. Further, zinc ion and ZnO nanoparticle clearly suppressed hemolytic activity in P. aeruginosa. Transcriptome analyses showed that ZnO nanoparticle induced zinc cation efflux pump czc operon, porin genes (oprD and opdT), and Pseudomonas type III repressor A ptrA, while repressed pyocyanin-related phz operon, which partially explains the phenotypic changes. Overall, ZnO nanoparticle is a potential candidate for use in an antivirulence approach against persistent P. aeruginosa infection.
2015-05-25 | GSE46947 | GEO
Project description:Surfing motility is a novel form of surface adaptation exhibited by the nosocomial pathogen, Pseudomonas aeruginosa, in the presence of the glycoprotein mucin that is found in high abundance at mucosal surfaces especially the lungs of cystic fibrosis and bronchiectasis patients. Here we investigated the adaptive antibiotic resistance of P. aeruginosa under conditions in which surfing occurs compared to cells undergoing swimming. P. aeruginosa surfing cells were significantly more resistant to several classes of antibiotics including aminoglycosides, carbapenems, polymyxins, and fluroquinolones. This was confirmed by incorporation of antibiotics into growth medium, which revealed a concentration-dependent inhibition of surfing motility that occurred at concentrations much higher than those needed to inhibit swimming. To investigate the basis of resistance, RNA-Seq was performed and revealed that surfing influenced the expression of numerous genes. Included amongst genes dysregulated under surfing conditions were multiple genes from the Pseudomonas resistome, which are known to affect antibiotic resistance when mutated. Screening transposon mutants in these surfing-dysregulated resistome genes revealed that several of these mutants exhibited changes in susceptibility to one or more antibiotics under surfing conditions, consistent with a contribution to the observed adaptive resistance. In particular, several mutants in resistome genes, including armR, recG, atpB, clpS, nuoB, and certain hypothetical genes such as PA5130, PA3576 and PA4292, showed contributions to broad-spectrum resistance under surfing conditions and could be complemented by their respective cloned genes. Therefore, we propose that surfing adaption led to extensive multidrug adaptive resistance as a result of the collective dysregulation of diverse genes.
2018-06-26 | GSE110044 | GEO
Project description:Pseudomonas aeruginosa colonises the upper airway of cystic fibrosis (CF) patients, providing a reservoir of host-adapted genotypes that subsequently establish chronic lung infection. We previously experimentally-evolved P. aeruginosa in a murine model of respiratory tract infection and observed mutations in pmrB that promoted establishment and persistence of infection. Here we show that mutations in pmrB, which encodes the sensor kinase of the PmrAB two-component system, are acquired early in infection and increase resistance to the host antimicrobial lysozyme. Proteomic analysis of pmrB mutants reveal downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance and phenazine production, and upregulation of proteins involved in adherence, lysozyme resistance and inhibition of the chloride ion channel CFTR, relative to wild-type strain LESB65. Accordingly, pmrB mutants show enhanced adherence to airway epithelial cells and downregulate host CFTR expression. P. aeruginosa pmrB mutations are found in CF patient isolates and are associated with the same phenotypes, but are subject to an evolutionary trade-off: enhanced colonisation potential, resistance to host defences and CFTR inhibition, but concomitant increased susceptibility to antibiotics.
2018-07-11 | PXD009705 | Pride
Project description:We compared the dynamics and mechanisms of resistance development to ceftazidime, meropenem, ciprofloxacin, and ceftolozane-tazobactam in wild-type (PAO1) and mutator (PAOMS, M-bM-^HM-^FmutS) P. aeruginosa. The strains were incubated for 24 h with 0.5 to 64M-CM-^W MICs of each antibiotic in triplicate experiments. The tubes from the highest antibiotic concentration showing growth were reinoculated in fresh medium containing concentrations up to 64M-CM-^W MIC for 7 consecutive days. The susceptibility profiles and resistance mechanisms were assessed in two isolated colonies from each step, antibiotic, and strain. Ceftolozane-tazobactam-resistant mutants were further characterized by whole-genome analysis through RNA sequencing (RNA-seq). The development of high-level resistance was fastest for ceftazidime, followed by meropenem and ciprofloxacin. None of the mutants selected with these antibiotics showed cross-resistance to ceftolozane-tazobactam. On the other hand, ceftolozane-tazobactam resistance development was much slower, and high-level resistance was observed for the mutator strain only. PAO1 derivatives that were moderately resistant (MICs, 4 to 8 ug/ml) to ceftolozane-tazobactam showed only 2 to 4 mutations, which determined global pleiotropic effects associated with a severe fitness cost. High-level-resistant (MICs, 32 to 128 ug/ml) PAOMS derivatives showed 45 to 53 mutations. Major changes in the global gene expression profiles were detected in all mutants, but only PAOMS mutants showed ampC overexpression, which was caused by dacB or ampR mutations. Moreover, all PAOMS mutants contained 1 to 4 mutations in the conserved residues of AmpC (F147L, Q157R, G183D, E247K, or V356I). Complementation studies revealed that these mutations greatly increased ceftolozane-tazobactam and ceftazidime MICs but reduced those of piperacillin-tazobactam and imipenem, compared to those in wild-type ampC. Therefore, the development of high-level resistance to ceftolozane-tazobactam appears to occur efficiently only in a P. aeruginosa mutator background, in which multiple mutations lead to overexpression and structural modifications of AmpC. Mutants of Pseudomonas aeroginosa PAO1 and PAO1 M-bM-^HM-^FmutS against Ceftolozane-tazobactam were generated and analysed using RNA-Seq
2014-06-12 | E-GEOD-58390 | biostudies-arrayexpress
Project description:The ParS/ParR two component regulatory system plays important roles for multidrug resistance in Pseudomonas aeruginosa. In this study we report RNA-seq analyses of the transcriptomes of P. aeruginosa PAO1 wild type and par mutants growing in a minimal medium containing 2% casamino acids. This has allowed the quantification of PAO1 transcriptome, and further defines the regulon that is dependent on the ParS/ParR system for expression. Our RNA-seq analysis produced the first estimates of absolute transcript abundance for the 5570 coding genes in P. aeruginosa PAO1. Comparative transcriptomics of P. aeruginosa PAO1 and par mutants identified a total of 464 genes regulated by ParS and ParR. Results also showed that mutations in the parS/parR system abolished the expression of the mexEF-oprN operon by down-regulating the regulatory gene mexS. In addition to affecting drug resistance genes, transcripts of quorum sensing genes (rhlIR and pqsABCDE-phnAB), were significantly up-regulated in both parS and parR mutants. Consistent with these results, a significant portion of the ParS/ParR regulated genes belonged to the MexEF-OprN and quorum sensing regulons. Deletion of par genes also lead to overproduction of phenazines and increased swarming motility, consistent with the up-regulation of quorum sensing genes. Our results established a link among ParS/ParR, MexEF-OprN and quorum sensing in Pseudomonas aeruginosa. Based on these results, we propose a model to illustrate the relationship among these regulatory systems in P. aeruginosa. A total of 9 samples were analyzed in AB medium + 2% casamino acids, Pseudomonas aeruginosa PAO1 wild type strain (3 replicates); Pseudomonas aeruginosa parS mutant (3 replicates); Pseudomonas aeruginosa parR mutant (3 replicates).
2016-02-26 | E-GEOD-44681 | biostudies-arrayexpress
Project description:The design of novel antibiotics that break antimicrobial resistance relies on a profound understanding of their mechanism of action. While it has been shown that the cellular effects of antibiotics cluster according to their molecular targets, we investigated whether compounds binding to different sites of the same target can be differentiated by their transcriptome or metabolome signatures. The effects of three fluoroquinolones, two aminocoumarins and two cystobactamids, all inhibiting bacterial gyrase, on Pseudomonas aeruginosa at sub-inhibitory concentrations were captured by RNA sequencing.
2021-05-03 | GSE166602 | GEO
Project description:Previous synthesized Pt NPs were selected to evaluate the influences on bacterial resistance, and a typical pathogenic microbe P. aeruginosa was chosen as model bacteria. After 60-day PtNPs exposure, we found under 12.5 μg/mL of platinum nanoparticles (PtNPs) exposure for ~7200 generations, the IC50 of evolved Pseudomonas aeruginosa PAO1 to imipenem (IPM) and ciprofloxacin (CIP) reduced 77.0% and 87.8%, respectively. Interestingly, long-term of PtNPs exposure arose the bacterial susceptibility on antibiotics. We then performed gene expression profiling analysis using data obtained from RNA-seq.
2023-12-01 | GSE218408 | GEO
Project description:The surge of antimicrobial resistance in recent decades threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic intracellular accumulation, thus making the discovery of novel drugs with whole cell antibacterial activity very challenging. We adapted PROSPECT, a genome-wide, target-based, whole cell screening strategy, to take a focused approach to discover small molecule probes with specific activity against engineered P. aeruginosa mutants depleted for essential proteins localized at the outer membrane. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic studies identified a novel link between OprL and the non-essential, outer membrane β barrel protein, OprH, to modulate BRD1401 activity. BRD1401 directly bound to OprH to disrupt the known interaction between OprH and lipopolysaccharide (LPS) in vitro and in whole bacteria. OprH also biochemically interacted with OprL, thus providing a link between outer membrane and peptidoglycan in P. aeruginosa. Thus, a whole cell, multiplexed screen against P. aeruginosa identified a species-specific inhibitor and probe molecule that revealed novel pathogen biology.
2024-03-15 | GSE252756 | GEO