Abstract
BackgroundAutophagy has been shown recently to play an important role in the intracellular survival of several pathogenic bacteria. In this study, we investigated the effect of a novel small-molecule autophagy-inducing agent, AR-12, on the survival of Francisella tularensis, the causative bacterium of tularemia in humans and a potential bioterrorism agent, in macrophages.Methods and resultsOur results show that AR-12 induces autophagy in THP-1 macrophages, as indicated by increased autophagosome formation, and potently inhibits the intracellular survival of F. tularensis (type A strain, Schu S4) and F. novicida in macrophages in association with increased bacterial co-localization with autophagosomes. The effect of AR-12 on intracellular F. novicida was fully reversed in the presence of the autophagy inhibitor, 3-methyl adenine or the lysosome inhibitor, chloroquine. Intracellular F. novicida were not susceptible to the inhibitory activity of AR-12 added at 12 h post-infection in THP-1 macrophages, and this lack of susceptibility was independent of the intracellular location of bacteria.ConclusionTogether, AR-12 represents a proof-of-principle that intracellular F. tularensis can be eradicated by small-molecule agents that target innate immunity.
Highlights
Autophagy has been shown recently to play an important role in the intracellular survival of several pathogenic bacteria
Our findings show that induction of autophagy is an effective approach for the control of intracellular F. tularensis in macrophages and suggest that AR-12 can serve as a scaffold for the development of more potent autophagy-inducing antibacterial agents
AR-12 induces autophagy in human macrophages without causing cytotoxicity AR-12 is an orally bioavailable small-molecule inhibitor of phosphoinositide-dependent kinase (PDK)-1 that was derived by structural modification of the cyclooxygenase2 (COX-2) inhibitor, celecoxib, but is devoid of COX-2inhibitory activity [20]
Summary
Autophagy has been shown recently to play an important role in the intracellular survival of several pathogenic bacteria. We investigated the effect of a novel smallmolecule autophagy-inducing agent, AR-12, on the survival of Francisella tularensis, the causative bacterium of tularemia in humans and a potential bioterrorism agent, in macrophages. Inhalation of bacteria causes the most severe form of the disease, pneumonic tularemia, which has a mortality rate as high as 60 percent in the absence of appropriate treatment [6,7,8]. Because of the potential to inflict severe disease in a large number of people with an aerosolized form of the bacteria, F. tularensis is classified in Category A of potential biological warfare agents by the U.S Centers for Disease Control and Prevention [9,10]. In the absence of an U.S Food and Drug Administration-approved vaccine and in light of the potential existence of antibiotic-resistant strains of F. tularensis created in the early 1990s [9,10,11], the development of new antibacterial agents with novel mechanisms against F. tularensis has become a priority for public safety
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