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Simvastatin and ML141 Decrease Intracellular Streptococcus pyogenes Infection

[ Vol. 20 , Issue. 9 ]

Author(s):

Lindy Caffo, Bria L. Sneed, Caroline Burcham, Katie Reed, Nathan C. Hahn, Samantha Bell, Christopher Downham, Christopher R. Fullenkamp, Teague D. Evans, Teague K. Drinnon, Derron Bishop, Heather A. Bruns, John L. McKillip, Robert E. Sammelson and Susan A. McDowell*   Pages 733 - 744 ( 12 )

Abstract:


Background: Recurrent pharyngotonsillitis due to Streptococcus pyogenes develops regardless of whether infecting strains are resistant or susceptible to first-line antimicrobials. Causation for recurrent infection is associated with use of first-line antimicrobials that fail to penetrate deep tissue and host cell membranes, enabling intracellular S. pyogenes to survive throughout repeated rounds of antimicrobial therapy.

Objective: To determine whether simvastatin, a therapeutic approved for use in treatment of hypercholesterolemia, and ML141, a first-in-class small molecule inhibitor with specificity for human CDC42, limit host cell invasion by S. pyogenes.

Methods: Assays to assess host cell invasion, bactericidal activity, host cell viability, actin depolymerization, and fibronectin binding were performed using the RAW 267.4 macrophage cell line and human umbilical vein endothelial cells (HUVEC) infected with S. pyogenes (90-226) and treated with simvastatin, ML141, structural analogs of ML141, or vehicle control.

Results: Simvastatin and ML141 decreased intracellular infection by S. pyogenes in a dose-dependent manner. Inhibition by simvastatin persisted following 1 h washout whereas inhibition by ML141 was reversed. During S. pyogenes infection, actin stress fibers depolymerized in vehicle control treated cells, yet remained intact in simvastatin and in ML141 treated cells. Consistent with previous characterization of ML141, simvastatin decreased host cell binding to fibronectin. Structural analogs of ML141, designated as the RSM series, decreased intracellular infection through non-cytotoxic, non-bactericidal mechanisms.

Conclusion: Our findings demonstrate the potential of repurposing simvastatin and of developing CDC42-targeted therapeutics for eradicating intracellular S. pyogenes infection to break the cycle of recurrent infection through a host-directed approach.

Keywords:

Antimicrobial therapy, antimicrobials, Streptococcus pyogenes, simvastatin, fibronectin, HUVEC.

Affiliation:

Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Indiana University School of Medicine - Muncie Campus, Muncie, IN, 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306, Ball State University, RH 105, 2100 West Riverside Avenue, Muncie, Indiana 47306



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