Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge

Antimicrobial Agents and Chemotherapy
Ky V HoangK M Ainslie

Abstract

Francisella tularensiscauses tularemia and is a potential biothreat. Given the limited antibiotics for treating tularemia and the possible use of antibiotic-resistant strains as a biowarfare agent, new antibacterial agents are needed. AR-12 is an FDA-approved investigational new drug (IND) compound that induces autophagy and has shown host-directed, broad-spectrum activityin vitroagainstSalmonella entericaserovar Typhimurium andF. tularensis We have shown that AR-12 encapsulated within acetalated dextran (Ace-DEX) microparticles (AR-12/MPs) significantly reduces host cell cytotoxicity compared to that with free AR-12, while retaining the ability to controlS.Typhimurium within infected human macrophages. In the present study, the toxicity and efficacy of AR-12/MPs in controlling virulent type AF. tularensisSchuS4 infection were examinedin vitroandin vivo No significant toxicity of blank MPs or AR-12/MPs was observed in lung histology sections when the formulations were given intranasally to uninfected mice. In histology sections from the lungs of intranasally infected mice treated with the formulations, increased macrophage infiltration was observed for AR-12/MPs, with or without suboptimal gentamicin treatment, but not for blan...Continue Reading

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Citations

Sep 21, 2016·Virulence·Kristie D Goughenour, Chad A Rappleye
Dec 16, 2017·Scientific Reports·Basant A AbdulrahmanHermann M Schatzl
Jun 3, 2020·Antimicrobial Agents and Chemotherapy·Shaoyan ZhangHaiqing Chu
Sep 8, 2019·International Journal for Parasitology. Drugs and Drug Resistance·M Shamim Hasan ZahidKristy M Ainslie
Apr 30, 2021·Chemical Communications : Chem Comm·Shiqi WangHélder A Santos
Jun 6, 2021·FEMS Microbiology Letters·M Shamim Hasan ZahidKristy M Ainslie

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