No abstract

The emergence of resistance to antibiotics is a serious problem often related to suboptimal drug dosing; such suboptimal dosing results in the preferential killing of drug-susceptible microbial subpopulations, allowing amplification of drug-resistant microbial subpopulations. We determined the effect that fluctuating concentrations of quinolone drugs have on both the total population and the resistant subpopulation of Pseudomonas aeruginosa, by employing, over a 48-h period, human pharmacokinetics and multiple regimens in an in vitro-infection model. All data were simultaneously modeled by use of 3 parallel inhomogeneous differential equations. Model parameters were used to derive the minimal, or breakpoint, drug exposure necessary to suppress amplification of the resistant subpopulation. In a prospective-validation study, we found that a drug exposure near to but below the calculated breakpoint amplified the resistant subpopulation, whereas a drug exposure at the breakpoint suppressed it. This approach allows delineation of target drug exposures (area under the concentration/time curve for 24 h : minimal inhibitory concentration [AUC(24) : MIC] = 190) that will suppress amplification of the antibiotic-resistant subpopulation, thereby preserving the susceptibility of target pathogens.

Salinity stress enhances reactive oxygen species (ROS) accumulation by activating the transcription of NADPH oxidase genes such as RbohD, thus mediating plant developmental processes, including seed germination. However, how salinity triggers the expression of ROSmetabolism-related genes and represses seed germination has not yet been fully addressed. In this study, we show that Abscisic Acid-Insensitive 4 (ABI4), a key component in abscisic acid (ABA) signaling, directly combines with RbohD and Vitamin C Defective 2 (VTC2), the key genes involved in ROS production and scavenging, to modulate ROS metabolism during seed germination under salinity stress. Salinity-induced ABI4 enhances RbohD expression by physically interacting with its promoter, and subsequently promotes ROS accumulation, thus resulting in cell membrane damage and a decrease in seed vigor. Additional genetic evidence indicated that the rbohd mutant largely rescues the salt-hypersensitive phenotype of ABI4 overexpression seeds. Consistently, the abi4/vtc2 double mutant showed the salt-sensitive phenotype, similar to the vtc2 mutant, suggesting that both RbohD and VTC2 are epistatic to ABI4 genetically. Altogether, these results suggest that the salt-induced RbohD transcription and ROS accumulation is dependent on ABI4, and that the ABI4-RbohD/VTC2 regulatory module integrates both ROS metabolism and cell membrane integrity, ultimately repressing seed germination under salinity stress.