57 research outputs found
Clinical implications of reduced susceptibility to fluoroquinolones in paediatric Shigella sonnei and Shigella flexneri infections.
OBJECTIVES: We aimed to quantify the impact of fluoroquinolone resistance on the clinical outcome of paediatric shigellosis patients treated with fluoroquinolones in southern Vietnam. Such information is important to inform therapeutic management for infections caused by this increasingly drug-resistant pathogen, responsible for high morbidity and mortality in young children globally. METHODS: Clinical information and bacterial isolates were derived from a randomized controlled trial comparing gatifloxacin with ciprofloxacin for the treatment of paediatric shigellosis. Time-kill experiments were performed to evaluate the impact of MIC on the in vitro growth of Shigella and Cox regression modelling was used to compare clinical outcome between treatments and Shigella species. RESULTS: Shigella flexneri patients treated with gatifloxacin had significantly worse outcomes than those treated with ciprofloxacin. However, the MICs of fluoroquinolones were not significantly associated with poorer outcome. The presence of S83L and A87T mutations in the gyrA gene significantly increased MICs of fluoroquinolones. Finally, elevated MICs and the presence of the qnrS gene allowed Shigella to replicate efficiently in vitro in high concentrations of ciprofloxacin. CONCLUSIONS: We found that below the CLSI breakpoint, there was no association between MIC and clinical outcome in paediatric shigellosis infections. However, S. flexneri patients had worse clinical outcomes when treated with gatifloxacin in this study regardless of MIC. Additionally, Shigella harbouring the qnrS gene are able to replicate efficiently in high concentrations of ciprofloxacin and we hypothesize that such strains possess a competitive advantage against fluoroquinolone-susceptible strains due to enhanced shedding and transmission
Cyclic enkephalin-deltorphin hybrids containing a carbonyl bridge: structure and opioid activity
Six hybrid N-ureidoethylamides of octapeptides in which
an N-terminal cyclic structure related to enkephalin was
elongated by a C-terminal fragment of deltorphin were
synthesized on MBHA resin. The synthetic procedure involved
deprotection of Boc groups with HCl/dioxane and
cleavage of the peptide resin with 45 % TFA in DCM. d-
Lys and d-Orn were incorporated in position 2, and Lys,
Orn, Dab, or Dap in position 5. The side chains of the
dibasic amino function were protected with the Fmoc
group. This protection was removed by treatment with
55 % piperidine in DMF, and cyclization was achieved
by treatment with bis-(4-nitrophenyl)carbonate. Using
various combinations of dibasic amino acids, peptides
containing a 17-, 18-, 19- or 20-membered ring structure
were obtained. The peptides were tested in the
guinea-pig ileum (GPI) and mouse vas deferens (MVD)
assays. Diverse opioid activities were observed, depending
on the size of the ring. Extension of the enkephalin
sequence at the C-terminus by a deltorphin fragment resulted
in a change of receptor selectivity in favor of the
δ receptor. The conformational propensities of selected
peptides were determined using the EDMC method in
conjunction with data derived from NMR experiments
carried out in water. This approach allowed proper examination of the dynamical behavior of these small peptides. The results were compared with those obtained
earlier with corresponding N-(ureidoethyl)pentapeptide
amides
In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues
[Image: see text] In this study the μ opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH(2)) and Dmt(1)-DALDA (Dmt-d-Arg-Phe-Lys-NH(2), Dmt = 2′,6′-dimethyltyrosine) were glycosylated at the N- or C-terminus. Subsequently, the modified peptides were subjected to in vitro and in vivo evaluation. In contrast to the N-terminally modified peptide (3), all peptide analogues derivatized at the C-terminus (4–7) proved to possess high affinity and agonist potency at both MOR and DOR (δ opioid receptor). Results of the Caco-2 monolayer permeation, as well as in vitro blood–brain barrier model experiments, showed that, in the case of compound 4, the glycosylation only slightly diminished the lumen-to-blood and blood-to-lumen transport. Altogether, these experiments were indicative of transcellular transport but not active transport. In vivo assays demonstrated that the peptides were capable of (i) crossing the blood–brain barrier (BBB) and (ii) activating both the spinal ascending as well as the descending opioid pathways, as determined by the tail-flick and hot-plate assays, respectively. In contrast to the highly selective MOR agonist Dmt(1)-DALDA 1, compounds 4–7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects
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