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Paradoxical Effect of Caspofungin: Reduced Activity against Candida albicans at High Drug Concentrations. David A. Stevens, 2004.Resistance problems with caspofungin, an echinocandin inhibitor of fungal cell wall glucan synthesis, have been rare . We noted paradoxical turbid growth of Candida albicans isolates in broth in some high (supra-MIC) concentrations . Among isolates submitted for susceptibility testing and screened at drug concentrations up to 12.5 µg/ml, the frequency was 16% . Analysis of the turbid growth indicated slowing of growth in the presence of drug but with numbers of CFU up to 72% those of drug-free controls . Clearing of growth again by the highest drug concentrations produced a quadriphasic pattern in a tube dilution series . Cells growing at high drug concentrations were not resistant on retesting but showed the paradoxical effect of the parent . Among a selected series of isolates tested at concentrations up to 50 µg/ml, an additional 53% showed a "mini-paradoxical effect": no turbid growth but incomplete killing at high concentrations (supra-minimum fungicidal concentration) . These effects were reproducible; medium dependent in extent; noted in macro- and microdilution, in the presence or absence of serum, and on agar containing drug (but not when drug concentrations were not constant, as in agar diffusion); not seen with other echinocandins and less commonly in other Candida species; and not due to destruction of drug in tubes showing the effect . Cooperative enhancement of inhibition by a second drug could eradicate the effect . We postulate that high drug concentrations derepress or activate resistance mechanisms . The abilities of subpopulations to survive at high drug concentrations could have in vivo consequences . Up-Regulated Expression of the cbbI and cbbII Operons during Photoheterotrophic Growth of a Ribulose 1,5-Bisphosphate Carboxylase-Oxygenase Deletion Mutant of Rhodobacter sphaeroides. Stephanie A. Smith, 2002.In a Rhodobacter sphaeroides ribulose 1,5-bisphosphate carboxylase-oxygenase deletion strain that requires an exogenous electron donor for photoheterotrophic growth, transcription of the genes of the Calvin-Benson-Bassham (CBB) cycle was increased . This finding pointed to a potential physiological effector that enhances the capability of the positive transcriptional activator CbbR to mediate cbb transcription . This effector is most likely ribulose 1,5-bisphosphate or a metabolite derived from this CBB pathway intermediate . Formaldehyde-Detoxifying Role of the Tetrahydromethanopterin-Linked Pathway in Methylobacterium extorquens AM1. Christopher J. Marx, 2003.The facultative methylotroph Methylobacterium extorquens AM1 possesses two pterin-dependent pathways for C1 transfer between formaldehyde and formate, the tetrahydrofolate (H4F)-linked pathway and the tetrahydromethanopterin (H4MPT)-linked pathway . Both pathways are required for growth on C1 substrates; however, mutants defective for the H4MPT pathway reveal a unique phenotype of being inhibited by methanol during growth on multicarbon compounds such as succinate. It has been previously proposed that this methanol-sensitive phenotype is due to the inability to effectively detoxify formaldehyde produced from methanol . Here we present a comparative physiological characterization of four mutants defective in the H4MPT pathway and place them into three different phenotypic classes that are concordant with the biochemical roles of the respective enzymes . We demonstrate that the analogous H4F pathway present in M. extorquens AM1 cannot fulfill the formaldehyde detoxification function, while a heterologously expressed pathway linked to glutathione and NAD+ can successfully substitute for the H4MPT pathway . Additionally, null mutants were generated in genes previously thought to be essential, indicating that the H4MPT pathway is not absolutely required during growth on multicarbon compounds . These results define the role of the H4MPT pathway as the primary formaldehyde oxidation and detoxification pathway in M . extorquens AM1 . Population Dynamics of Vibrio fischeri during Infection of Euprymna scolopes. Jessica McCann, 2003.The luminous bacterium Vibrio fischeri colonizes a specialized light-emitting organ within its squid host, Euprymna scolopes . Newly hatched juvenile squid must acquire their symbiont from ambient seawater, where the bacteria are present at low concentrations . To understand the population dynamics of V . fischeri during colonization more fully, we used mini-Tn7 transposons to mark bacteria with antibiotic resistance so that the growth of their progeny could be monitored . When grown in culture, there was no detectable metabolic burden on V . fischeri cells carrying the transposon, which inserts in single copy in a specific intergenic region of the V . fischeri genome . Strains marked with mini-Tn7 also appeared to be equivalent to the wild type in their ability to infect and multiply within the host during coinoculation experiments . Studies of the early stages of colonization suggested that only a few bacteria became associated with symbiotic tissue when animals were exposed for a discrete period (3 h) to an inoculum of V . fischeri cells equivalent to natural population levels; nevertheless, all these hosts became infected . When three differentially marked strains of V . fischeri were coincubated with juvenile squid, the number of strains recovered from an individual symbiotic organ was directly dependent on the size of the inoculum . Further, these results indicated that, when exposed to low numbers of V . fischeri, the host may become colonized by only one or a few bacterial cells, suggesting that symbiotic infection is highly efficient .
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