Benzoxazoles, phthalazinones, and arylurea-based compounds with IMPDH-independent antibacterial activity against Francisella tularensis [PublishAheadOfPrint]

Francisella tularensis is the causative agent of tularemia and a potential biowarfare agent. The virulence of F. tularensis is decreased by deletion of guaB, the gene encoding inosine monophosphate dehydrogenase (IMPDH), suggesting that this enzyme is a target for antibacterial design. Here we report that F. tularensis growth is blocked by inhibitors of bacterial IMPDHs. Seventeen compounds from two different frameworks, designated D and Q, display antibacterial activity with minimum inhibitory concentrations less than 1 μM. These compounds are also active against intracellular infections. Surprisingly, antibacterial activity does not correlate with IMPDH inhibition. In addition, the presence of guanine does not affect the antibacterial activity of most compounds, nor does the deletion of guaB. These observations suggest that antibacterial activity derives from inhibition of another target(s). Moreover, D compounds only display antibacterial activity against F. tularensis, suggesting the presence of a unique target or uptake mechanism. A guaB mutant resistant to compound D73 contained a missense mutation (Gly45Cys) in nuoB, which encodes a subunit of bacterial complex I. Over-expression of the mutant nuoB conferred resistance to D73 in both wild-type and guaB strains. This strain was not resistant to Q compounds, suggesting that a different off-target mechanism operates for these compounds. Several Q compounds are also effective against Mycobacterium tuberculosis, where a second target has also been implicated in addition to IMPDH. The fortuitous presence of multiple targets with overlapping structure-activity relationships presents an intriguing opportunity for the development of robust antibiotics that may avoid the emergence of resistance.

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