Pharmaceutical and mutational interference with virulence of Salmonella enterica serovar typhimurium

Abstract: Within the species Salmonella enterica are a diverse range of bacteria that can cause illness in humans and many animals. Salmonellae are extremely versatile and can adapt to a variety of environments and hosts. Typhoid and paratyphoid fever, caused by human-restricted S. enterica serovars Typhi and Paratyphi are common in the developing world. An increased resistance to the first line antibiotics has been recorded amongst salmonellae, which makes the basic and applied research aiming to farther the understanding of the disease and developing new regimes of treatment even more important. We showed that salicylidene acylhydrazides are able to inhibit the activity of virulence-associated type III secretion systems SPI1 and SPI2 in Salmonella enterica serovar Typhimurium. The compounds strongly affected Salmonella pathogenicity island (SPI) 1 activity and also SPI2-mediated intracellular bacterial replication in murine macrophage-like cells. In addition, two of the compounds significantly inhibited bacterial motility and expression of extracellular flagellin. We also found that the proton pump inhibitor omeprazole had a bacteriostatic effect on intracellular replication of S. Typhimurium mediated by virulence-associated SPI2 T3SS. We could demonstrate that S. Typhimurium rapidly acquires mutations in the putative transport protein SbmA, reducing the susceptibility of the bacteria to antimicrobial peptide PR-39 without an obvious fitness cost. We report for the first time that expression of thioredoxin 1 in the facultative intracellular pathogen S. Typhimurium is induced at conditions that prevail during intracellular infection and that thioredoxin 1 is necessary for proper T3SS expression, protein secretion and virulence. Our findings define an entirely new functional niche for thioredoxin 1 and demonstrate a new level of inter-connection between core genome functions and horizontally-acquired virulence genes in bacteria.