The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells.
Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium Coxiella burnetii in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-C. burnetii activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process.
Department of Biomedical Sciences, Oregon State University, Corvallis, Oregon, USA.
Kelsi M
KM
Sandoz
Department of Biomedical Sciences, Oregon State University, Corvallis, Oregon, USA.
William G
WG
Valiant
Department of Biomedical Sciences, Oregon State University, Corvallis, Oregon, USA.
Steven G
SG
Eriksen
Siga Technologies, Inc., Corvallis, Oregon, USA.
Dennis E
DE
Hruby
Siga Technologies, Inc., Corvallis, Oregon, USA.
Robert D
RD
Allen
Department of Biomedical Sciences, Oregon State University, Corvallis, Oregon, USA rockeyd@orst.edu.
Daniel D
DD
Rockey
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002689:Chlamydia / Q000187:drug effects* / Q000254:growth & development; D002690:Chlamydia Infections / Q000188:drug therapy* / Q000382:microbiology; D016997:Coxiella burnetii / Q000187:drug effects; D016680:Genome, Bacterial; D006801:Humans; D002479:Inclusion Bodies / Q000382:microbiology*; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D013890:Thiourea / Q000494:pharmacology*
D000998:Antiviral Agents; D008055:Lipids; C000601048:ST-669; D013890:Thiourea