Abstract
Characterization of expression profile of organisms in response to antimicrobials provides important information on the potential mechanism of action of the drugs. The special expression signature can be used to predict whether other drugs act on the same target. Here, the common response of Shigella flexneri to two inhibitors of RNA polymerase was examined using gene expression profiling. Consistent with similar effects of the two drugs, the gene expression profiles indicated that responses of the bacteria to these drugs were roughly the same, with 225 genes affected commonly. Of them, 88 were induced and 137 were repressed. Real-time PCR was performed for selected genes to verify the microarray results. Analysis of the expression data revealed that more than 30% of the plasmid-encoded genes on the array were up-regulated by the antibiotics including virF regulon, other virulence-related genes, and genes responsible for plasmid replication, maintenance, and transfer. In addition, some chromosome-encoded genes involved in virulence and genes acquired from horizontal transfer were also significantly up-regulated. However, the expression of genes encoding the beta-subunit of RNA polymerase was increased moderately. The repressed genes include those that code for products associated with the ribosome, citrate cycle, glycolysis, thiamine biosynthesis, purine metabolism, fructose metabolism, mannose metabolism, and cold shock proteins. This study demonstrates that the two antibiotics induce rapid cessation of RNA synthesis resulting in inhibition of translation components. It also indicates that the production of virulence factors involved in intercellular dissemination, tissue invasion and inflammatory destruction may be enhanced through derepressing horizontal transfer genes by the drugs.
Highlights
Shigella species are facultative, gram-negative intracellular pathogens responsible for endemic shigellosis, a major worldwide health problem in developing countries
We investigated the regulation of virulence genes by RNA synthesis inhibitors, RP and RX, in S. flexneri, and we defined the common expression signature elicited by the two compounds using whole-genome DNA microarray technology
The growth curve of S. flexneri shows that RX suppresses bacterial growth to a higher degree than RP after 90 min of exposure, especially at concentrations no higher than 16MIC, indicating that the antimicrobial activity of RX is more potent and rapid than that of RP
Summary
Gram-negative intracellular pathogens responsible for endemic shigellosis, a major worldwide health problem in developing countries. Antimicrobial agents are used to control infection; the increase in antibiotic resistance of pathogens is threatening to undermine treatment of shigellosis [2]. RP is used in combination with other antibiotics to control Staphylococcus aureus infection [4]. RX is approved in other countries for the treatment of a variety of gastrointestinal disorders, including acute bacterial infection or colonization by organisms such as Clostridium difficile, small bowel intestinal overgrowth, irritable bowel syndrome, inflammatory bowel disease, pouchitis and colonic diverticular disease [5]. Due to the minimal absorption of RX the risk of adverse effects, systemic toxicity, and drug interactions is correspondingly low compared with systemically available antibiotics
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