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 ΔguaB 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 ΔguaB 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.
Pharmacology, Toxicology and Pharmaceutical Science
2
15%
Biochemistry, Genetics and Molecular Biology
2
15%
Agricultural and Biological Sciences
2
15%
Immunology and Microbiology
2
15%
Other
0
0%
Unknown
2
15%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 5. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 31 October 2019.
All research outputs
#9,369,854
of 32,463,143 outputs
Outputs from Antimicrobial Agents and Chemotherapy
#8,656
of 18,354 outputs
Outputs of similar age
#108,261
of 346,130 outputs
Outputs of similar age from Antimicrobial Agents and Chemotherapy
#183
of 215 outputs
Altmetric has tracked 32,463,143 research outputs across all sources so far. This one has received more attention than most of these and is in the 70th percentile.
So far Altmetric has tracked 18,354 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.5. This one has gotten more attention than average, scoring higher than 52% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 346,130 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 68% of its contemporaries.
We're also able to compare this research output to 215 others from the same source and published within six weeks on either side of this one. This one is in the 13th percentile – i.e., 13% of its contemporaries scored the same or lower than it.
