167 research outputs found
Repurposing MK-8245 as a Quorum Sensing Inhibitor to Suppress Virulence and Potentiate Antibiotic Activity in Pseudomonas aeruginosa
No full textBackground/Objectives: The rise in multidrug-resistant pathogens such as Pseudomonas aeruginosa (PA), coupled with declining antibiotic development, underscores the need for innovative therapeutic strategies. Repurposing approved drugs provides advantages of safety and rapid development. Since quorum sensing (QS) controls key virulence traits in PA, targeting this pathway represents a promising antivirulence approach. This study aimed to identify and repurpose existing drugs as QS inhibitors. Methods: An in silico docking screen of 3000 FDA-approved or clinically tested compounds was performed against the C4-HSL receptor RhlR. Seventeen candidates were tested in the laboratory strain PAO1 for lactone-dependent signaling inhibition. The most active compound, MK-8245, was further evaluated for effects on growth, cytotoxicity, lactone release, biofilm formation, pyocyanin, elastase, rhamnolipids, and swarming motility. Its activity was also assessed in 20 clinical PA isolates. Results: MK-8245 (40 μM) reduced QS-regulated gene expression by ~60% without affecting viability. In PAO1, it inhibited rhamnolipids (60%), pyocyanin (40%), elastase (25%), biofilm formation, and swarming motility (25%). MK-8245 also enhanced the efficacy of imipenem against biofilms. In clinical isolates, it consistently decreased lactone release (~60%), pyocyanin (~50%), rhamnolipids (~40%), biofilm formation (~30%), and swarming motility (~25%). Conclusions: MK-8245 emerges as a promising antivirulence candidate against P. aeruginosa. By disrupting QS signaling and impairing multiple virulence factors, it attenuates pathogenicity without bactericidal pressure. Its synergy with standard antibiotics and consistent activity in clinical isolates highlight its translational potential and warrant further preclinical evaluation
Decreased summer drought affects plant productivity and soil carbon dynamics in a Mediterranean woodland
No full textPrecipitation patterns are expected to change in the Mediterranean region within the next decades, with projected decreases in total rainfall and increases in extreme events. We manipulated precipitation patterns in a Mediterranean woodland, dominated by Arbutus unedo L., to study the effects of changing precipitation regimes on above-ground net primary production (ANPP) and soil C dynamics, specifically plant-derived C input to soil and soil respiration (SR). Experimental plots were exposed to either a 20 % reduction of throughfall or to water addition targeted at maintaining soil water content above a minimum of 10 % v/v. Treatments were compared to control plots which received ambient precipitation. Enhanced soil moisture during summer months highly stimulated annual stem primary production, litter fall, SR and net annual plant-derived C input to soil which on average increased by 130 %, 26 %, 58 % and 220 %, respectively, as compared to the control. In contrast, the 20 % reduction in throughfall (equivalent to 10 % reduction in precipitation) did not significantly change soil moisture at the site, and therefore did not significantly affect ANPP or SR. We conclude that minor changes (around 10 % reduction) in precipitation amount are not likely to significantly affect ANPP or soil C dynamics in Mediterranean woodlands. However, if summer rain increases, C cycling will significantly accelerate but soil C stocks are not likely to be changed in the short-term. More studies involving modelling of long-term C dynamics are needed to predict if the estimated increases in soil C input under wet conditions is going to be sustained and if labile C is being substituted to stable C, with a negative effect on long-term soil C stocks. © Author(s) 2011
Precipitation pulses enhance respiration of Mediterranean ecosystems: the balance between organic and inorganic components of increased soil CO2 efflux
No full textIn regions characterized by arid seasons, such as the Mediterranean basin, soil moisture is a major driver of ecosystem CO(2) efflux during periods of drought stress. Here, a rain event can induce a disproportional respiratory pulse, releasing an amount of CO(2) to the atmosphere that may significantly contribute to the annual ecosystem carbon balance. The mechanisms behind this pulse are unclear, and it is still unknown whether it is due to the stimulation of autotrophic, heterotrophic and/or inorganic CO(2) fluxes. On the Mediterranean island of Pianosa, eddy flux measurements showed respiratory pulses after rain events following prolonged drought periods, which occurred in the summer of 2003 and 2006. To investigate the mechanisms of this observed enhanced respiration fluxes and partition of the soil CO(2) sources, two water manipulation experiments were performed. The first was designed to estimate the effect of soil rewetting on soil CO(2) efflux, in the different ecosystem types existing on the island (i.e. woodland, ex-agricultural and Mediterranean shrubland). The second was a soil CO(2) partitioning experiment to investigate the relative contribution of inorganic and organic CO(2) sources to soil respiration, under dry and wet soil conditions. Our results suggest that the pulse in the CO(2) efflux is primarily due to the enhancement of heterotrophic respiration, likely caused by the degradation of easily decomposable substrates, accumulated in soils during the dry period. In fact, the vegetation at the site was senescent and did not play any significant role in CO(2) exchange, as suggested by the absence of diurnal CO(2) uptake in eddy covariance measurements. In addition, soil rewetting did not significantly enhance inorganic CO(2) efflux
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