Inhibition of lipoprotein sorting in Francisella tularensis: a potential target of resazomycins, a novel family of antibiotics.
Tularemia is a potentially fatal illness caused by the bacterium Francisella tularensis. Inhalation of less than 10 bacteria results in an acute pneumonia with an associated mortality rate of 30-60% if left untreated. Due to the potential use of F. tularensis as a weapon of bioterrorism and development of antibiotic resistance, new antibiotics are being sought against this pathogen. We have identified a novel family of resazurin-based compounds named resazomycins which exhibit antimicrobial activity against F. tularensis and Neisseria gonorrhoeae. In order to proceed with in vivo testing of resazomycins, their mechanism of action must be determined. A recent study has shown that while F. tularensis and N. gonorrhoeae are taxonomically distinct from one another, they share a similar lipoprotein sorting system, LolDF. This complex differs from the LolCDE sorting complex commonly found in other Gram negative bacteria which indicates this system may be a target of resazomycins. To determine whether resazurin inhibits the function of LolDF we will express the genes that encode for the E. coli lipoprotein sorting system (lolCDE) in F. tularensis to see if we can confer resistance to resazurin. Experimentation thus far has proven to be unsuccessful in trying to generate this construct since overexpression of lolCDE in E. coli is lethal. To limit expression of these genes until the plasmid has been transferred into F. tularensis, we will explore different inducible expression systems. Future investigations will focus on cloning the E. coli lolCDE genes into a Francisella shuttle vector containing a tetracycline-regulatable promoter.
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