title: Brodimoprim: effects of subminimal inhibitory concentrations on virulence traits of respiratory and urinary tract pathogens, and on plasmid transfer and stability.
abstract: The effects of brodimoprim, a new trimethoprim analogue, on several virulence traits of respiratory and urinary tract pathogens exposed to sub-lethal levels of the drug was studied. Adherence to tracheal epithelial cells was inhibited by brodimoprim in Klebsiella pneumoniae (41-67% reduction), Moraxella catarrhalis (87-90%) and Haemophilus influenzae (0-53%), while in Streptococcus pneumoniae binding was unaffected. With buccal epithelial cells the comparison between treated and control bacteria indicated statistically significant reduction in adherence with both S.pneumoniae and H.influenzae, (P < 0.015). With M.catarrhalis and Streptococcus pyogenes only marginal changes were detected (P > 0.05). Exoenzyme and capsule production were assessed in at least three isolates of diverse respiratory pathogens grown in the presence of sub-lethal levels of the new agent. The drug affected protease and beta-hemolysin (alpha-toxin) production in both oxacillin-susceptible and -resistant S.aureus. On the contrary, synthesis of lipase, DNase, coagulase, and beta-lactamase (S.aureus), pneumolysin (S.pneumoniae), streptolysin S, DNase, and protease (S.pyogenes), capsule (K.pneumoniae, H.influenzae and S.pneumoniae), and beta-lactamase (K.pneumoniae, H.influenzae and M.catarrhalis) were not inhibited by subminimal inhibitory concentrations (sub-MICs) of the drug. Finally, motility was blocked in urinary pathogens E.coli, P.mirabilis and P.aeruginosa, while in this latter microorganism pigment production was also affected. High molecular weight low-copy F'lac, and low molecular weight high-copy pHSG298 plasmids were eliminated from E.coli treated with sub-MIC concentrations of brodimoprim. The incidence and cured cells ranged from 9% for F'lac to 23% for pHSG298. F'lac transfer was also inhibited by the drug. When conjugation was carried out with bacteria exposed to brodimoprim (5XMIC), a reduction (50%) in the number of recombinants was noted in comparison to the control. The fact that brodimoprim interferes with the expression of some virulence traits, in particular with adherence, at sub-MIC levels may assist the drug in eradicating respiratory pathogens from the epithelial lining, thus diminishing the probability of reinfection.
authors.affiliation: Institute of Microbiology, University of Genoa, Medical School, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Marchese
authors.forename: E A
authors.initials: EA
authors.lastname: Debbia
authors.forename: S
authors.initials: S
authors.lastname: Massaro
authors.forename: U
authors.initials: U
authors.lastname: Campora
authors.forename: G
authors.initials: G
authors.lastname: Schito
mesh_terms: D001422:Bacterial Adhesion / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002610:Cheek; D010450:Endopeptidases / Q000378:metabolism; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology; D006460:Hemolysin Proteins / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D001936:Moraxella catarrhalis / Q000187:drug effects / Q000201:enzymology; D010957:Plasmids; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology; D013301:Streptolysins / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000382:microbiology*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D005493:Folic Acid Antagonists; D006460:Hemolysin Proteins; D013301:Streptolysins; D014295:Trimethoprim; D010450:Endopeptidases; D001618:beta-Lactamases; C037079:brodimoprim