Rifalazil Pretreatment of Mammalian Cell Cultures Prevents Subsequent Chlamydia Infection

Abstract

Chlamydia species are widely disseminated obligate intracellular pathogens that primarily cause urogenital, ocular, and respiratory infections. In these studies, we show that exposing mammalian cells to antibacterial agents prior to Chlamydia inoculation protects the host cells against subsequent challenge by chlamydiae (the protective effect [PE]). Rifalazil exhibited a considerably stronger PE than did azithromycin, rifampin, doxycycline, and ofloxacin. Specifically, 0.002 g/ml rifalazil incubated for 1 day with a monolayer of McCoy cells was sufficient to protect against a challenge 2 days later with Chlamydia trachomatis serovar D (UW-3). The PE was observed with five different mammalian cell lines and with a variety of C. trachomatis and Chlamydia pneumoniae isolates. The duration of the PE was 6 to 12 days for rifalazil (depending on the cell line), a maximum of 3 days for azithromycin, and less than a day for the other drugs tested. For rifalazil, the PE was shown to be mediated by inhibition of the chlamydial RNA polymerase since mutants with altered RNA polymerases had correspondingly altered PEs. These results suggest that rifalazil may be unique in its ability to prevent infection with obligate intracellular pathogens for a considerable time after treatment. This characteristic may be of particular public health value in reducing reinfection with chlamydiae.

Rifalazil and Other Benzoxazinorifamycins in the Treatment of Chlamydia‐Based Persistent Infections

“…Thus, rifalazil's long-lasting effect could offer a unique advantage in effectively treating chlamydia infections, compared with existing approved agents [104]. Recent experiments show that rifalazil retains activity in cell culture at all stages of the chlamydia life cycle, including invasion and/or uptake of elementary bodies, reticulate body replication, and persistent cells.…”

Tuberculosis and the risk of infection with other intracellular bacteria: a population-based study

“…Also, in vitro and in vivo studies have shown that rifamycins such as rifampin have activity against C. trachomatis , so their use in anti-TB therapy may also prevent C. trachomatis infection [39, 40]. This could have potential public health implications for preventing this disease in high-risk groups where recurrent C. trachomatis infection, a major cause of pelvic inflammatory disease, ectopic pregnancy, chronic pelvic pain and infertility, is common [41, 42]. Alternatively, immunological responses against M. tuberculosis may have a partially protective effect on C. trachomatis infections, mediated by macrophage activation.…”

Rifalazil Retains Activity Against Rifampin-resistant Mutants of Chlamydia pneumoniae

“…The determination of protective concentrations after exposure to rifamycins was as described [27]. Briefly, mammalian cells were treated as in the MIC testing, exposed to rifamycins for 24 hours, centrifuged, washed, and incubated in fresh antibacterial-free medium, until elementary bodies of C. pneumoniae were added either 2 or 7 days of incubation in antibacterial-free medium.…”

“…The NCEs had 2ϳ8 fold lower MCC 3 s compared with rifalazil. The protective concentration was determined by exposing mammalian cells to the indicated compounds, and then growing the mammalian cells for either two or seven subsequent days of incubation in antibacterial-free medium prior to infection, as previously described [27]. The antibacterial concentration affording protection was again 2ϳ8 fold lower for NCEs than for rifalazil.…”