EXCEED THE SPACE PROVIDED. Bacteroides comprise the predominant component of the indigenous human intestinal microflora where they account for about 30% of the total bacterial population. Although these organisms perform a variety of physiological activities necessary for normal function of the host, several species also are opportunistic pathogens which tend to dominate intra-abdominal, pelvic and many post-operative infections. Successful treatment of anaerobic infections requires the use of antimicrobial therapy yet the Bacteroides are highly drug resistantdue to a combination of inherent physiological properties and acquired drug resistance genes. This complex pattern of antibiotic resistance can severely complicate treatment of infections and lead to life threatening situations. In addition to this immediate threat, the high numbers of Bacteroides in the gut provide the opportunity to contact and interact with a variety of other indigenous flora (e.g Escherichia coli) or transientspecies (e.g. Salmonella) with whom genetic exchange may be possible. Thus, Bacteroides may act as reservoirs of antibiotic resistance determinants and transmissible genetic elements. The long term goal of this project is to secure a basic understanding of the genetic and physiological mechanisms that control Bacteroides antibiotic resistance. This goal embraces the need to elucidate fundamental genetic mechanismsof gene transfer and recombination since they play an important role in the dissemination of drug resistance genes. The goal will be addressed in the current application by our continued investigation irito the mechanisms controlling dissemination of the extended-spectrum R-lactamase,CfxA. Our central..hypothesis is that the rapid emergence of cefoxitin resistance was in large part due to the disseminationof cfxA and it is the unique genetic and biochemical features of elements such as Tn4555 that promote this dissemination. In.the current application the following specific questions will address this central hypothesis: 1, does the novel protein-mediated, chromosomal targeting mechanismofTn4555 insertion enhance the insertion, stability and/or maintenance of this type of antibiotic resistance transposon; 2, is excision of Tn45S5 a key point of control that governs mobilization and disseminationof the element; 3, what are the critical features of the tetracycline signal transduction pathway that regulate Tn4555 transpositionand mobilization, and allow rapid disseminationof the element. PERFORMANCE SITE ========================================Section End===========================================
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