ABSTRACT
Valley fever (coccidioidomycosis) is a disease caused by inhalation of spores from the soil-dwelling Coccidioides fungal species. The disease is endemic to semiarid areas in the western USA and parts of Central and South America. The region of interest for this study, Kern County, California, accounts for approximately 14% of the reported valley fever cases in the USA each year. It is hypothesized that the weather conditions that foster the growth and dispersal of the fungus influence the number of cases in the endemic area. This study uses regression-based analysis to model and assess the seasonal relationships between valley fever incidence and climatic variables including concurrent and lagged precipitation, temperature, Palmer Drought Severity Index, wind speed, and PM10 using data from 2000 to 2015. We find statistically significant links between disease incidence and climate conditions in Kern County, California. The best performing seasonal model explains up to 76% of the variability in fall valley fever incidence based on concurrent and antecedent climate conditions. Findings are consistent with previous studies, suggesting that antecedent precipitation is an important predictor of disease. The significant relationships found support the "grow and blow" hypothesis for climate-related coccidioidomycosis incidence risk that was originally developed for Arizona.
Subject(s)
Coccidioides/growth & development , Coccidioidomycosis/epidemiology , Temperature , Weather , California/epidemiology , IncidenceABSTRACT
Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4-thiadiazolyl ring leads to oxazolidinone analogues 5 having potent antibacterial activity against both gram-positive and gram-negative organisms. Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Phenols/chemistry , Thiadiazoles/chemistry , Acetamides/chemical synthesis , Acetamides/chemistry , Acetamides/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Linezolid , Microbial Sensitivity Tests , Oxazolidinones/chemistry , Rats , Structure-Activity Relationship , Thioacetamide/chemical synthesis , Thioacetamide/chemistry , Thioacetamide/pharmacologyABSTRACT
The oxazolidinones are a novel class of antimicrobial agents that target protein synthesis in a wide spectrum of gram-positive and anaerobic bacteria. The oxazolidinone PNU-100766 (linezolid) inhibits the binding of fMet-tRNA to 70S ribosomes. Mutations to oxazolidinone resistance in Halobacterium halobium, Staphylococcus aureus, and Escherichia coli map at or near domain V of the 23S rRNA, suggesting that the oxazolidinones may target the peptidyl transferase region responsible for binding fMet-tRNA. This study demonstrates that the potency of oxazolidinones corresponds to increased inhibition of fMet-tRNA binding. The inhibition of fMet-tRNA binding is competitive with respect to the fMet-tRNA concentration, suggesting that the P site is affected. The fMet-tRNA reacts with puromycin to form peptide bonds in the presence of elongation factor P (EF-P), which is needed for optimum specificity and efficiency of peptide bond synthesis. Oxazolidinone inhibition of the P site was evaluated by first binding fMet-tRNA to the A site, followed by translocation to the P site with EF-G. All three of the oxazolidinones used in this study inhibited translocation of fMet-tRNA. We propose that the oxazolidinones target the ribosomal P site and pleiotropically affect fMet-tRNA binding, EF-P stimulated synthesis of peptide bonds, and, most markedly, EF-G-mediated translocation of fMet-tRNA into the P site.
