The pipeline for new antibiotics is drying out in times where old antibiotics are losing effect due to increasing bacterial resistance. Focus on so-call "non-antibiotics" has therefore increased. Non-antibiotics are drugs indicated for non-infectious disease, but also possess antibacterial properties. Sertraline is a prescritive drug indicated treatment of for mental disorders, but is also documented to increase the sensitivity of bacteria to antibiotics, in particular tetracycline. The present study investigated the direct effect of sertraline and effect when combined with tetracycline on morphology, antibiotic sensitivity, conjugation frequency and global transcriptome of an avian pathogenic E. coli. The results revealed synergy between sertraline and tetracycline, of which mininmal inhibitory concentration (MIC) for the latter could be reduced from 64 to 2 µg/ml in the presence of ½ MIC of sertraline. Sertraline also dramatically changed cell morphology of E. coli, resulting in elongation of the cells. The transciptome analysis revealed that sertraline combined with tetracycline resulted in significant regulation of 803 genes, which were not significantly regulated under individual sertraline or tetracycline exposure. The genes were distributed among all functional classes, but were in particularly up-regulated in translation, replication and repair, cell wall and lipid metabolism. Furthermore, plasmids associated genes were significantly down-regulated and conjugation frequencies were decreased in the presence of sertraline.
In conclusion, this study provide novel insight into the changes in gene regulation of E. coli when exposed to sertraline and tetracycline combined. The clinical impact of sertraline on infections due to antibiotic resistant E. coli remain to be studied in vivo, which will reveal if combination treatment of sertraline with tetracycline can act as a "here-and-now" solution to multiresistant, Gram-negative infections.