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Biomedical subjects

B Hearn

Publications and source records attributed to B Hearn.

7 recordsLinked to original sources
PubMed2003

Delivery of antimicrobials into parasites.

To eliminate apicomplexan parasites, inhibitory compounds must cross host cell, parasitophorous vacuole, and parasite membranes and cyst walls, making delivery challenging. Here, we show that short oligomers of arginine enter Toxoplasma gondii tachyzoites and encysted bradyzoites. Triclosan, which inhibits enoyl-ACP reductase (ENR), conjugated to arginine oligomers enters extracellular tachyzoites, host cells, tachyzoites inside parasitophorous vacuoles within host cells, extracellular bradyzoites, and bradyzoites within cysts. We identify, clone, and sequence T. gondii enr and produce and characterize enzymatically active, recombinant ENR. This enzyme has the requisite amino acids to bind triclosan. Triclosan released after conjugation to octaarginine via a readily hydrolyzable ester linkage inhibits ENR activity, tachyzoites in vitro, and tachyzoites in mice. Delivery of an inhibitor to a microorganism via conjugation to octaarginine provides an approach to transporting antimicrobials and other small molecules to sequestered parasites, a model system to characterize transport across multiple membrane barriers and structures, a widely applicable paradigm for treatment of active and encysted apicomplexan and other infections, and a generic proof of principle for a mechanism of medicine delivery.

Amino Acid Sequence↗
PubMed1997

Plasmodium falciparum: cyanide-resistant oxygen consumption.

It has been hypothesized that Plasmodium parasites utilize a branched chain respiratory pathway, consisting of a classical cyanide-sensitive branch and an alternative cyanide-resistant branch. To further explore this hypothesis, the effect of cyanide on Plasmodium falciparum was determined using a polarographic assay. The rate of oxygen consumption by saponin-freed parasites was approximately 5% that of control human white blood cells or of Toxoplasma gondii, consistent with an anabolic role for P. falciparum respiration. However, while all of the oxygen consumption of the control white blood cells and of T. gondii could be inhibited by cyanide, 25% of the oxygen consumption of the P. falciparum parasites was found to be insensitive to high concentrations of cyanide. The cyanide-resistant portion of the parasite oxygen consumption was completely inhibited by two inhibitors of alternative oxidase activities in other systems, propyl gallate and salicyclhydroxamic acid. These studies provide the first direct evidence for a branched chain respiratory pathway in P. falciparum. Furthermore, salicyclhydroxamic acid, propyl gallate, and related inhibitors of alternative oxidase activities were shown to inhibit the growth of P. falciparum in vitro. These results support the need for further investigation of alternative oxidase activity as an antimalarial chemotherapeutic target.

Animals↗
PubMed1987

Organisms isolated from severe odontogenic soft tissue infections: their sensitivities to cefotetan and seven other antibiotics, and implications for therapy and prophylaxis.

Cefotetan is a new cephamycin antibiotic characterised by excellent B-lactamase stability and anti-anaerobe activity, coupled with a long half life of 3-4 h which permits twice daily dosage. A clinical trial of cefotetan in the treatment of severe oro-facial infections is presented, together with a detailed analysis of the causative organisms and their sensitivities to eight antibiotics. 50/50 patients achieved clinical cure with a treatment regime comprising cefotetan therapy and incision and drainage, with patients being transferred to oral cephradine for the final phase of therapy. Side effects were minimal and there were no instances of relapse. Significant resistance among alpha-haemolytic streptococci and bacteroides organisms to penicillin was observed. The streptococci were resistant due to mechanisms other than beta-lactamase production. In the light of these findings and the reports of other workers it is suggested that penicillin V may no longer be the most appropriate drug for endocarditis prophylaxis, despite the most recent recommendations of the American Heart Association. Furthermore, if penicillin V is used for this purpose, a penicillin free interval of 6-8 weeks may be inadequate before this drug is used. Cefotetan is not suitable for prophylaxis against endocarditis.

Acute Disease↗