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  • American Society for Microbiology  (2)
  • Pharmacy  (2)
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  • American Society for Microbiology  (2)
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  • Pharmacy  (2)
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  • 1
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 7 ( 2015-07), p. 3789-3799
    Abstract: CpxRA is a two-component signal transduction system (2CSTS) found in many drug-resistant Gram-negative bacteria. In response to periplasmic stress, CpxA autophosphorylates and donates a phosphoryl group to its cognate response regulator, CpxR. Phosphorylated CpxR (CpxR-P) upregulates genes involved in membrane repair and downregulates multiple genes that encode virulence factors, which are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in Salmonella enterica serovar Typhimurium and Haemophilus ducreyi are avirulent in mice and humans, respectively. Thus, the activation of CpxRA has high potential as a novel antimicrobial/antivirulence strategy. Using a series of Escherichia coli strains containing a CpxR-P-responsive lacZ reporter and deletions in genes encoding CpxRA system components, we developed and validated a novel cell-based high-throughput screen (HTS) for CpxRA activators. A screen of 36,000 compounds yielded one hit compound that increased reporter activity in wild-type cells. This is the first report of a compound that activates, rather than inhibits, a 2CSTS. The activity profile of the compound against CpxRA pathway mutants in the presence of glucose suggested that the compound inhibits CpxA phosphatase activity. We confirmed that the compound induced the accumulation of CpxR-P in treated cells. Although the hit compound contained a nitro group, a derivative lacking this group retained activity in serum and had lower cytotoxicity than that of the initial hit. This HTS is amenable for the screening of larger libraries to find compounds that activate CpxRA by other mechanisms, and it could be adapted to find activators of other two-component systems.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
    Library Location Call Number Volume/Issue/Year Availability
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  • 2
    Online Resource
    Online Resource
    American Society for Microbiology ; 1998
    In:  Antimicrobial Agents and Chemotherapy Vol. 42, No. 10 ( 1998-10), p. 2690-2693
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 42, No. 10 ( 1998-10), p. 2690-2693
    Abstract: Protegrins, potent antimicrobial peptides found in porcine leukocytes, have activity against the sexually transmitted pathogens Neisseria gonorrhoeae , Chlamydia trachomatis , and human immunodeficiency virus type 1. We tested synthetic protegrin 1 (PG-1) for activity against nine isolates of Haemophilus ducreyi , the etiologic agent of chancroid. The test organisms included CIP 542 (the type strain), 35000HP (a human-passaged variant of 35000), 35000HP-RSM2 (an isogenic d - glycero - d - manno -heptosyltransferase mutant of 35000HP), and six clinical isolates. The isolates were epidemiologically unrelated, represented three Hin dIII ribotypes, and had varying antimicrobial resistance patterns. In bactericidal assays, five isolates were rapidly killed by synthetic PG-1. In radial diffusion assays, all nine isolates were exquisitely sensitive to PG-1. These data highlight the potential of protegrins for development as topical agents to prevent many sexually transmitted diseases, including chancroid.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1998
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
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