A study examining the influence of TolC on AcrA, AcrR, and MarR1 mutants indicates that functional TolC is required for the operation of the AcrAB efflux system and for the expression of the Mar phenotype. That the effect of TolC on the AcrAB pump is not regulatory in nature is shown by studies measuring the influence of a tolC::Tn10 insertion mutation on the expression of an acrA::lacZ reporter fusion. These results are compatible with the hypothesis that TolC is a component of the AcrAB efflux complex.
Mice compromised by a burn wound injury and subjected to a fatal infection with Pseudomonas aeruginosa were administered a single dose of a Pseudomonas aeruginosa phage cocktail consisting of three different P. aeruginosa phages by three different routes: the intramuscular (i.m.), subcutaneous (s.c.), or intraperitoneal (i.p.) route. The results of these studies indicated that a single dose of the P. aeruginosa phage cocktail could significantly decrease the mortality of thermally injured, P. aeruginosa-infected mice (from 6% survival without treatment to 22 to 87% survival with treatment) and that the route of administration was particularly important to the efficacy of the treatment, with the i.p. route providing the most significant (87%) protection. The pharmacokinetics of phage delivery to the blood, spleen, and liver suggested that the phages administered by the i.p. route were delivered at a higher dose, were delivered earlier, and were delivered for a more sustained period of time than the phages administered by the i.m. or s.c. route, which may explain the differences in the efficacies of these three different routes of administration.Pseudomonas aeruginosa plays a prominent role as an etiological agent of serious infections in patients with burn wounds. Acute burn wounds cause a breach in the protective skin barrier and suppress the immune system, rendering the patients highly susceptible to bacterial infection. P. aeruginosa colonization of severe burn wounds and its rapid proliferation within the damaged tissues often lead to disseminated infections, resulting in bacteremia and septic shock (8,20) and high rates of mortality and morbidity. Treatment of such infections is confounded by the innate and acquired resistance of P. aeruginosa to many antimicrobials (8,15). It has been estimated that at least 50% of all deaths caused by burns are the result of infection (8), and untreatable infections have become a tragically frequent occurrence in patients infected with P. aeruginosa (9). Hence, the development of new therapeutic and prophylactic strategies for the control of bacterial infection in patients with burn wounds is needed.An alternative or supplement to antibiotic therapy, which is currently being reexamined, is the use of bacterial viruses (phage/bacteriophage) to target bacterial infections, i.e., phage therapy (13, 16-18, 22, 29, 30-32). Soothill examined the ability of bacteriophage to prevent the rejection of skin grafts of experimentally infected guinea pigs (27). His findings demonstrated that the phage-treated grafts were protected in six of seven cases, while untreated grafts failed uniformly, suggesting that phage might be useful for the prevention of P. aeruginosa infections in patients with burn wounds. However, while multiple studies have demonstrated the benefits of phage therapy for a variety of bacterial infections in animal model systems (3-7, 10, 14, 19, 23-26, 33-35), little documentation exists with regard to the treatment of burn wound infections (2). In the study described ...
The ‘Appelmans protocol’ is used by Eastern European researchers to generate therapeutic phages with novel lytic host ranges. Phage cocktails are iteratively grown on a suite of mostly refractory bacterial isolates until the evolved cocktail can lyse the phage-resistant strains. To study this process, we developed a modified protocol using a cocktail of three Pseudomonas phages and a suite of eight phage-resistant (including a common laboratory strain) and two phage-sensitive Pseudomona aeruginosa strains. After 30 rounds of selection, phages were isolated from the evolved cocktail with greatly increased host range. Control experiments with individual phages showed little host-range expansion, and genomic analysis of one of the broad-host-range output phages showed its recombinatorial origin, suggesting that the protocol works predominantly via recombination between phages. The Appelmans protocol may be useful for evolving therapeutic phage cocktails as required from well-defined precursor phages.
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