Abstract
The constant emergence of antibiotic multi-resistant pathogens is a concern worldwide. An alternative for bacterial treatment using nM concentrations of tellurite was recently proposed to boost antibiotic-toxicity and a synergistic effect of tellurite/cefotaxime (CTX) was described. In this work, the molecular mechanism underlying this phenomenon is proposed. Global changes of the transcriptional profile of Escherichia coli exposed to tellurite/CTX were determined by DNA microarrays. Induction of a number of stress regulators (as SoxS), genes related to oxidative damage and membrane transporters was observed. Accordingly, increased tellurite adsorption/uptake and oxidative injuries to proteins and DNA were determined in cells exposed to the mixture of toxicants, suggesting that the tellurite-mediated CTX-potentiating effect is dependent, at least in part, on oxidative stress. Thus, the synergistic tellurite-mediated CTX-potentiating effect depends on increased tellurite uptake/adsorption which results in damage to proteins, DNA and probably other macromolecules. Our findings represent a contribution to the current knowledge of bacterial physiology under antibiotic stress and can be of great interest in the development of new antibiotic-potentiating strategies.
Highlights
Multi-antibiotic resistance in bacteria has become a public health concern and an important veterinary problem worldwide
In order to identify the cell pathways that are affected in response to tellurite, CTX and/or tellurite/CTX exposure, induced and repressed genes in each condition were grouped using Gene Ontology (GO) terms
Even though the concentration of tellurite used in this study was ten-fold lower than that in previous experiments [12], exposure to the toxicant still resulted in soxS gene induction (GeneID: 948567, 4.7 fold-change), along with that of others such as marR and dnaK (GeneIDs:945825 and 944750, each with almost 3 fold-change), related to metal response and oxidative stress, respectively [13,14] (Table S2 A)
Summary
Multi-antibiotic resistance in bacteria has become a public health concern and an important veterinary problem worldwide. Scientific and pharmaceutical efforts have been devoted to look for new antibiotics and to synthesize or modify existing ones. In spite of these efforts only one novel antibiotic has been introduced in the market during the last 50 years [1]. Increasing antibiotic toxicity in a synergistic manner combining those with chemical compounds or metals having different cellular targets are among the most promising ones. This strategy significantly reduces the probability of emergence of strains that are resistant simultaneously to both antibacterials. While bismuth thiols have been used to improve tobramycin effects [3], the combined administration of the complex desferrioxamine- gallium and gentamicin increased the toxicity against Pseudomonas aeruginosa [4]
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