Dissecting Colistin Resistance Mechanisms in Extensively Drug-Resistant Acinetobacter baumannii Clinical Isolates

Nosocomial infections with; Acinetobacter baumannii; are a global problem in intensive care units with high mortality rates. Increasing resistance to first- and second-line antibiotics has forced the use of colistin as last-resort treatment, and increasing development of colistin resistance in; A. baumannii; has been reported. We evaluated the transcriptional regulator PmrA as potential drug target to restore colistin efficacy in; A. baumannii; Deletion of; pmrA; restored colistin susceptibility in 10 of the 12 extensively drug-resistant; A. baumannii; clinical isolates studied, indicating the importance of PmrA in the drug resistance phenotype. However, two strains remained highly resistant, indicating that PmrA-mediated overexpression of the phosphoethanolamine (PetN) transferase PmrC is not the exclusive colistin resistance mechanism in; A. baumannii; A detailed genetic characterization revealed a new colistin resistance mechanism mediated by genetic integration of the insertion element IS; AbaI; upstream of the PmrC homolog EptA (93% identity), leading to its overexpression. We found that; eptA; was ubiquitously present in clinical strains belonging to the international clone 2, and IS; AbaI; integration upstream of; eptA; was required to mediate the colistin-resistant phenotype. In addition, we found a duplicated IS; AbaI; -; eptA; cassette in one isolate, indicating that this colistin resistance determinant may be embedded in a mobile genetic element. Our data disprove PmrA as a drug target for adjuvant therapy but highlight the importance of PetN transferase-mediated colistin resistance in clinical strains. We suggest that direct targeting of the homologous PetN transferases PmrC/EptA may have the potential to overcome colistin resistance in; A. baumannii; IMPORTANCE; The discovery of antibiotics revolutionized modern medicine and enabled us to cure previously deadly bacterial infections. However, a progressive increase in antibiotic resistance rates is a major and global threat for our health care system. Colistin represents one of our last-resort antibiotics that is still active against most Gram-negative bacterial pathogens, but increasing resistance is reported worldwide, in particular due to the plasmid-encoded protein MCR-1 present in pathogens such as; Escherichia coli; and; Klebsiella pneumoniae; Here, we showed that colistin resistance in; A. baumannii; , a top-priority pathogen causing deadly nosocomial infections, is mediated through different avenues that result in increased activity of homologous phosphoethanolamine (PetN) transferases. Considering that MCR-1 is also a PetN transferase, our findings indicate that PetN transferases might be the Achilles heel of superbugs and that direct targeting of them may have the potential to preserve the activity of polymyxin antibiotics

De la musicothérapie à la thérapie non-verbale : le modèle Benenzon et son évolution

National audienceAs a theoretical model of music therapy, the Benenzon model has constantly rethought itself and evolved towards what is now called: Benenzonian non-verbal therapy. In this article, we will try to draw its main outlines. We will see what are the theoretical foundations and key concepts such as Sound Identity (now Sensory Identity), No-out and Co-out, etc. We will discuss the therapist's particular position i in gand the ethics to which he refers and which guides his practice. We willthus understand that this approach is not only clinical, but more broadly a theoretical, philosophical, psychological and clinical model of non-verbal communicationModèle théorique de musicothérapie, le modèle Benenzon n’a cessé de se repenser et d’évoluer vers ce qui se nomme aujourd’hui: la thérapie non-verbale benenzonienne. Dans cet article, nous tenterons d’en tracer les principaux contours. Nous verrons quels en sont les fondements théoriques et les concepts clés tels que celui d’Identité Sonore (devenu aujourd’hui Identité Sensorielle), les Noout et les Co-out, etc. Nous aborderons le positionnement particulier du thérapeute et l’éthique à laquelle il se réfère et qui guidera sa pratique. Nous comprendrons ainsi que cette approche n’est pas uniquement clinique, mais qu’il s’agit plus largement d’un modèle théorique, philosophique, psychologique et clinique de la communication non-verbale

A novel synthesis of N-substituted α-Amino ketones

The thermolysis of ethyl azidoformate in enol trimethylsilyl ethers, followed by silica gel treatment, offers a new route to N-ethoxycarbonyl α-amino ketones. © 1983

δ-lactones from grignard reactions : Their isolation and structure characterization

Grignard reactions of 4-RC6H4COCHMe(CH2)2CO2Me (I; R = H, Me, F, Cl, Br) with MeCl in anhyd. THF at 60° for 40 min gave 65-81% yield of 0.64-0.70:1 mixts. of δ-lactones II (α-, β-Me; R as before). At 0° the reaction of I (R = F, Cl, Br) gave 38-48% of 0.45-0.51:1 mixts. of II (α-, β-Me; R = F, Cl, Br). The lactones were characterized by 13C and 1H NMR

FREE-SOLUTION CAPILLARY ELECTROPHORETIC RESOLUTION OF CHIRAL AMINO-ACIDS VIA DERIVATIZATION WITH HOMOCHIRAL ISOTHIOCYANATES .1.

Within the framework of a more general study aimed at the enantiomeric resolution of non-UV-absorbing chiral amino acids via derivatization with chiral isothiocyanates, we have examined the applicability of two such derivatizing agents, (S)-1-(1-naphthyl)ethyl isothiocyanate (SNEIT) and (S)-1-phenylethyl isothiocyanate (SAMBI), to the resolution of the enantiomers of alanine, phenylalanine, and valine in free-solution capillary electrophoresis (FSCE). Isothiocyanates have distinct advantages as chiral derivatizing agents in enantiospecific chromatographic analysis, and the two reagents were readily synthesized from commercially available reagents. SNEIT, previously not fully described in the literature, was characterized by rigorous physicochemical and spectroscopic means. The two diastereoisomeric thiourea derivatives of each amino acid were separated by FSCE. Heptakis-2,3,6-tri-O-methyl-beta-cyclodextrin was effective in assuring the solubility of the derivatives in the working buffer and was more efficient than beta-cyclodextrin in both dissolving the thioureas and improving the electrophoretic resolution. Enantiomeric pairs migrated in the order L before D. Under the conditions used SAMBI-derivatized amino acids had longer elution times than the corresponding SNEIT derivatives. The diastereomeric derivatives of valine and of phenylalanine had larger separation factors alpha than the corresponding SAMBI derivatives, while the derivatives of alanine had nearly identical alpha values with the two derivatizing agents. The two reagents may be advantageous in the enantiospecific analysis of amino acids, and it appears that further exploration of these and other similar reagents is warranted

Preparation of basic prolineamide derivatives of GE2270 and GE2270-like antibiotics

Title compds. [I; R1 = H, alkyl, dialkylaminoalkylene; X = alkylene, alkylenecarbonyl; R2 = amino, 5-6 membered N-heterocyclyl; R1R2 = atoms to form a (substituted) 5-6 membered heterocyclic ring; W1 = Ph; W2 = OH; or W1, W2 both = Me; X1 = H, Me; X2 = H, Me, MeOCH2; when both W1, W2 = Me, then X1 = Me and X2 = H], were prepd. Thus, GE2270 factor A3 was condensed with H-Ser-Pro-NHCH2CH2NEt2 hydrochloride (prepn. given) using Et3N/DPPA in DMF and the condensation product in THF was treated with Burgess reagent in CH2Cl2 followed by Me2CHOH quench and reflux to give I; (R1 = H; XR2 = CH2CH2NEt2; W1 = Ph; W2 = OH; X1 = Me; X2 = MeOCH2). The latter showed a min. inhibitory concn. of 0.06 \u3bcg/mL against Staphylococcus aureus

Allylic functionalization of 2,5- and 2,4-cyclohexadiene-1,3-dicarboxylates

A series of 2,4- and 2,5-cyclohexadiene-1,3-dicarboxylates were functionalized at the allylic position via oxidotion, (SeO2, PDC/t-BuOOH) and halogenation (NBS). The regiochemical outcome for different substrates and reactions was studied and the importance of factors such as reaction mechanism,steric hindrance and reaction intermediates stability was discussed