MAHONY JB, SONG X; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. E-1652.

McMaster University, St. Joseph's Healthcare, Hamilton, ON, Canada.

BACKGROUND: C. pneumoniae is a common cause of pharyngitis and pneumonia. Epidemiological studies have established an association between C. pneumoniae infection and coronary artery disease. We have evaluated a new rifamycin derivative, Rifalazil[TM] for antichlamydial activity and evaluated its effect on chlamydial gene expression. METHODS: MIC[90] for Rifalazil[TM] (ActivBiotics, Cambridge, MA), Doxycycline, Metronidazole and Isoniazid were determined for C. pneumoniae using HEp-2 cells and staining inclusions at 72 hr using FITC-conjugated anti-LPS monoclonal antibody. Transcription of 6 key chlamydial genes (ompA, hsp60, parB, hctA, ftsK, and 16S RNA) was measured at 24, 48, and 72 hr post infection by RT-PCR. RESULTS: MIC[90] for C. pneumoniae were as follows: Rifalazil[TM], 0.0002 ug/mL, Doxycycline, 0.2 ug/mL, Metronidazole, 800 ug/mL, and Isoniazid, 400 ug/mL. Synergism between either Metronidazole or Isoniazid and Rifalazil[TM] was unremarkable; Metronidazole (200-400 ug/mL) and Isoniazid (200-400 ug/mL) reduced the MIC[90] for Rifalazil[TM] by 2-4 fold. Both Rifalazil[TM] (0.0008 ug/mL) and Doxycycline (1 ug/mL) abolished the expression of key chlamydial genes involved in chromosomal condensation and partitioning (hctA, par B), and cytokinesis (ftsK) and downregulated expression of genes coding for the major outer membrane protein (ompA) and heat shock protein (hsp60) by 90%. Transcripts for 16S RNA were not affected by either Doxycycline or Rifalazil[TM]. Consclusions: Rifalazil[TM] has the lowest MIC[90] for C. pneumoniae (0.0002 ug/mL) of all previously reported antibiotics. The mechanism of inhibition appears to be at the transcriptional level turning off essential genes required for cell division. Due to its potent antichlamydial activity, Rifalazil[TM] may offer advantages over other antibiotics in the treatment of persistent chlamydial infections and may reduce the inflammation asssociated with C. pneumoniae infection by downregulating hsp60 expression.

Publication Types:

• Meeting Abstracts

Keywords:

• Anti-Bacterial Agents
• Cell Division
• Chlamydia Infections
• Chlamydophila pneumoniae
• Epidemiologic Studies
• Gene Expression
• KRM 1648
• Microbial Sensitivity Tests
• Reverse Transcriptase Polymerase Chain Reaction
• Rifamycins
• Transcription, Genetic
• genetics
• rifamycin SV

Other ID:

• GWAIDS0027801

UI: 102267425

From Meeting Abstracts