Drug repurposing has the potential to greatly reduce both the time and cost associated with developing new therapeutics for bacterial infections. The objective of this study was to identify a common host gene expression profile induced by multiple species of intracellular bacterial pathogens to search for clinically approved compounds that could potentially revert the pattern of gene expression in cell culture infection models. In this study, human THP-1 monocytes were differentiated into macrophage-like cells and infected with virulent Coxiella burnetii (Q fever). Microarrays were used to assess the change in host cell gene expression during infection. These results were combined with other publically available datasets of Francisella tularensis (tularaemia) and Burkholderia pseudomallei (melioidosis) infection of THP-1 cells. The datasets were normalized using RUV-rinv to remove unwanted variations. A comparison of the normalized datasets led to the identification of 56 differentially expressed genes (42 up, and 14 down-regulated) that were common to B. pseudomallei, F. tularensis and C. burnetii infections. These genes constituted a ‘host genetic signature’ common to infections by multiple species of bacterial pathogens. The publically accessible Connectivity Map database, which contains the cellular gene expression profiles of 1309 FDA approved compounds, was searched using the host genetic signature as a query through pattern-matching. A number of compounds were identified based on their ability to elicit a transcriptional profile that was significantly inversely correlated to the signature associated with bacterial infections in cell lines. These compounds provide potential candidates for the development of a novel host-directed therapeutic against bacterial pathogens.