A bacterial pathogen must be able to invade and multiply in its host. Host defenses, such as serum-killing and phagocytosis, successfully oppose the invader and where an infection becomes established, administration of antibiotics may provide additional time for the host to eliminate invading pathogen. These studies focus on the how the cell surface components of pathogenic bacteria function in resistance to host defense mechanisms and antibiotics. Escherichia coli, Salmonella typhimurium, and other Gram-negative bacteria become phenotypically resistant to a variety of unrelated antibiotics when grown in media containing 0.5~10 mM acetaminophen. The increased antibiotic resistance is due to the decreased expression of porin protein. This effect is similar, if not identical, to that seen when these same cells are grown in sodium salicylate. 56 Gram-negative strains, isolated as human pathogens, were grown in the presence of sodium salicylate and their sensitivity to each of four antibiotics tested [Cefoxitin, Ciprofloxacin, Norfloxacin, and Tetracycline All strains showed a minimally 4-fold increase in the minimal inhibitory concentration [MIC] of at least one antibiotic and most showed significant increase in the MIC of all four antibiotics studied. The 56 strains studied included species of Acinetobacter, Citrobacter, Enterobacter, Escherichia, Klebsiella, Proteus. Several genetic loci are involved in the regulation of the expression of the Escherichia coli outer membrane porins. The regulation of expression of Omp F in the outer membrane, various lacZ+ fusion strains were grown in the presence or absence of salicylate. The effect of salicylate on ompF expression was independent of the osmolarity of the medium. It was epistatic to the envZ3 and ompR331 osmoregulatory mutations. Like salicylate, these mutations, engender high constitutive levels of micF transcription and concomitant low levels of OmpF porin expression. These results showed that growth in salicylate severely decreases the translation of ompF by enhancing the expression of micF. In this respect, sal/-grown cells resemble marA or tolC mutant strains that have high levels of micF and low levels of OmpF. Dr. Foulds was detailed to the National Vaccine Program Office for part of the year [March 15-September 30] where he served as a policy analyst and scientific advisor to the program.
