Antibacterial agents specifically inhibiting lipopolysaccharide synthesis

The spread of antibiotic resistance in Gram-negative bacteria has sustained a continuing search for new agents with antibacterial activity against this important class of bacterial pathogen. Because the biosynthesis of lipopolysaccharide (LPS) is unique to Gram-negative bacteria and required by them for growth and virulence, attempts have been made to discover or design antibacterial agents acting at this site; however, no such agents have so far been developed. We now present definitive experimental data documenting design of the first member of the class of antibacterial compounds which specifically inhibit LPS synthesis. The target enzyme is 3-deoxy-D-manno-octulosonate cytidylytransferase (CMP-KDO synthetase), a cytoplasmic enzyme which activates 3-deoxy-D-manno-octulosonate (KDO) for incorporation into LPS. A specific inhibitor of CMP-KDO synthetase, alpha-C-(1,5-anhydro-7-amino-2,7-dideoxy-D-manno-heptopyranosyl)-carboxy late was designed using results of our studies of the purified enzyme. LPS synthesis ceased and lipid A precursor accumulated, causing growth stasis and perturbation of outer membrane structure and function, following delivery of the inhibitor to the intracellular target by a peptide carrier. Antibacterial action required an intact oligopeptide permease system and specific intracellular aminopeptidase activity to release inhibitor from the peptide prodrug.     

The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita

Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA. Dyskerin is also associated with telomerase RNA (hTR), which contains a H/ACA consensus sequence. Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3' 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.     

Maturation of the pineal melatonin rhythm in long- and short-day reared Djungarian hamsters

Summary Male Djungarian hamsters, reared under long (16L/8D) or short (10L/14D) days, were sacrificed at various ages during the day or night, or at night following a 30-min light pulse. The pineal melatonin rhythm matured similarly under long and short days by 20 days of age. The results are discussed in context of the hypothesis that melatonin mediates the photoperiod effects which forestall puberty in short-day reared hamsters.Supported by NIH research grant HD-05481.     

Maturation of the pineal melatonin rhythm in long- and short-day reared Djungarian hamsters

Male Djungarian hamsters, reared under long (16L/8D) or short (10L/14D) days, were sacrificed at various ages during the day or night, or at night following a 30-min light pulse. The pineal melatonin rhythm matured similarly under long and short days by 20 days of age. The results are discussed in context of the hypothesis that melatonin mediates the photoperiod effects which forestall puberty in short-day reared hamsters.     

Differential effects of lipids on the osmotic fragility of lysosomes

Summary The effect of a wide range of concentrations of oleic acid, oleyl alcohol and oleic acid methyl ester on lysosomal stability has been studied under both hypotonic and isoosmotic medium conditions. Both oleic acid and oleyl alcohol exhibited a biphasic interaction pattern with lysosomes; stabilizing at low concentrations and labilizing at high concentrations. Lysosome labilization by the ester required an initial lag period.Acknowledgment. We should like to thank Mr.David Ginzburg for the assistance he gave us during the 3 months he spent at our department as a summer student.     

Differential effects of lipids on the osmotic fragility of lysosomes.

The effect of a wide range of concentrations of oleic acid, oleyl alcohol and oleic acid methyl ester on lysosomal stability has been studied under both hypotonic and isoosmotic medium conditions. Both oleic acid and oleyl alcohol exhibited a biphasic interaction pattern with lysosomes; stabilizing at low concentrations and labilizing at high concentrations. Lysosome labilization by the ester required an initial lag period.