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Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens.

Czyż DM, Potluri LP, Jain-Gupta N, Riley SP, Martinez JJ, Steck TL, Crosson S, Shuman HA, Gabay JE - MBio (2014)

Bottom Line: Combining host- and pathogen-directed treatments is a strategy to decrease the emergence of drug-resistant intracellular bacterial pathogens.Importance: Although antibiotic treatment is often successful, it is becoming clear that alternatives to conventional pathogen-directed therapy must be developed in the face of increasing antibiotic resistance.Moreover, the costs and timing associated with the development of novel antimicrobials make repurposed FDA-approved drugs attractive host-targeted therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, USA Department of Microbiology, University of Chicago, Chicago, Illinois, USA.

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Related in: MedlinePlus

Genetic disruption of cholesterol homeostasis inhibits the intracellular growth of C. burnetii. (A) Images of NPC-1 shRNA-mediated inhibition of intracellular C. burnetii. Panels I and IV show Nomarski images of control (empty-vector shRNA) THP-1 cells and cells transfected with NPC-1 shRNA. Panels II and V show fluorescence signals generated from the shRNA vector. Panels III and VI show intracellular C. burnetii. For direct comparison of fluorescence signals, images were taken at a constant exposure. Scale bars, 100 µm. (B) Growth curve of C. burnetii in THP-1 cells transfected with the control and three different constructs of NPC-1 shRNA. Western blot of NPC-1 levels relative to those in an actin control in cells transfected with NPC-1 shRNA constructs and control shRNA.
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fig4: Genetic disruption of cholesterol homeostasis inhibits the intracellular growth of C. burnetii. (A) Images of NPC-1 shRNA-mediated inhibition of intracellular C. burnetii. Panels I and IV show Nomarski images of control (empty-vector shRNA) THP-1 cells and cells transfected with NPC-1 shRNA. Panels II and V show fluorescence signals generated from the shRNA vector. Panels III and VI show intracellular C. burnetii. For direct comparison of fluorescence signals, images were taken at a constant exposure. Scale bars, 100 µm. (B) Growth curve of C. burnetii in THP-1 cells transfected with the control and three different constructs of NPC-1 shRNA. Western blot of NPC-1 levels relative to those in an actin control in cells transfected with NPC-1 shRNA constructs and control shRNA.

Mentions: To independently evaluate the role of cholesterol trafficking in the intracellular growth of C. burnetii, we constructed THP-1 cell lines with decreased levels of NPC-1, a transporter that facilitates the export of cholesterol from late endosomes and lysosomes. We found that reducing the expression of NPC-1 decreased the intracellular growth of C. burnetii (Fig. 4A and B). We infer that the intracellular movement of cholesterol is a key determinant of C. burnetii growth that can be interrupted by a wide variety of FDA-approved drugs.


Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens.

Czyż DM, Potluri LP, Jain-Gupta N, Riley SP, Martinez JJ, Steck TL, Crosson S, Shuman HA, Gabay JE - MBio (2014)

Genetic disruption of cholesterol homeostasis inhibits the intracellular growth of C. burnetii. (A) Images of NPC-1 shRNA-mediated inhibition of intracellular C. burnetii. Panels I and IV show Nomarski images of control (empty-vector shRNA) THP-1 cells and cells transfected with NPC-1 shRNA. Panels II and V show fluorescence signals generated from the shRNA vector. Panels III and VI show intracellular C. burnetii. For direct comparison of fluorescence signals, images were taken at a constant exposure. Scale bars, 100 µm. (B) Growth curve of C. burnetii in THP-1 cells transfected with the control and three different constructs of NPC-1 shRNA. Western blot of NPC-1 levels relative to those in an actin control in cells transfected with NPC-1 shRNA constructs and control shRNA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128363&req=5

fig4: Genetic disruption of cholesterol homeostasis inhibits the intracellular growth of C. burnetii. (A) Images of NPC-1 shRNA-mediated inhibition of intracellular C. burnetii. Panels I and IV show Nomarski images of control (empty-vector shRNA) THP-1 cells and cells transfected with NPC-1 shRNA. Panels II and V show fluorescence signals generated from the shRNA vector. Panels III and VI show intracellular C. burnetii. For direct comparison of fluorescence signals, images were taken at a constant exposure. Scale bars, 100 µm. (B) Growth curve of C. burnetii in THP-1 cells transfected with the control and three different constructs of NPC-1 shRNA. Western blot of NPC-1 levels relative to those in an actin control in cells transfected with NPC-1 shRNA constructs and control shRNA.
Mentions: To independently evaluate the role of cholesterol trafficking in the intracellular growth of C. burnetii, we constructed THP-1 cell lines with decreased levels of NPC-1, a transporter that facilitates the export of cholesterol from late endosomes and lysosomes. We found that reducing the expression of NPC-1 decreased the intracellular growth of C. burnetii (Fig. 4A and B). We infer that the intracellular movement of cholesterol is a key determinant of C. burnetii growth that can be interrupted by a wide variety of FDA-approved drugs.

Bottom Line: Combining host- and pathogen-directed treatments is a strategy to decrease the emergence of drug-resistant intracellular bacterial pathogens.Importance: Although antibiotic treatment is often successful, it is becoming clear that alternatives to conventional pathogen-directed therapy must be developed in the face of increasing antibiotic resistance.Moreover, the costs and timing associated with the development of novel antimicrobials make repurposed FDA-approved drugs attractive host-targeted therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, USA Department of Microbiology, University of Chicago, Chicago, Illinois, USA.

Show MeSH
Related in: MedlinePlus