Enhancing the Antibiotic Antibacterial Effect by Sub Lethal Tellurite Concentrations: Tellurite and Cefotaxime Act Synergistically in Escherichia coli

The emergence of antibiotic-resistant pathogenic bacteria during the last decades has become a public health concern worldwide. Aiming to explore new alternatives to treat antibiotic-resistant bacteria and given that the tellurium oxyanion tellurite is highly toxic for most microorganisms, we evaluated the ability of sub lethal tellurite concentrations to strengthen the effect of several antibiotics. Tellurite, at nM or µM concentrations, increased importantly the toxicity of defined antibacterials. This was observed with both Gram negative and Gram positive bacteria, irrespective of the antibiotic or tellurite tolerance of the particular microorganism. The tellurite-mediated antibiotic-potentiating effect occurs in laboratory and clinical, uropathogenic Escherichia coli, especially with antibiotics disturbing the cell wall (ampicillin, cefotaxime) or protein synthesis (tetracycline, chloramphenicol, gentamicin). In particular, the effect of tellurite on the activity of the clinically-relevant, third-generation cephalosporin (cefotaxime), was evaluated. Cell viability assays showed that tellurite and cefotaxime act synergistically against E. coli. In conclusion, using tellurite like an adjuvant could be of great help to cope with several multi-resistant pathogens

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DNA, cell wall and general oxidative damage underlie the tellurite/cefotaxime synergistic effect in Escherichia coli.

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

Hydroxyl radical generation in <i>E. coli</i> exposed to CTX or Te/CTX.

<p><i>E. coli</i> was exposed for 3 h to tellurite/CTX (A) and to different antibiotic concentrations (B). As positive control, cells were exposed for 3 h to ampicillin. Units are expressed in µg ml⁻¹. The data correspond to a representative result of 3 independent trials.</p

Tellurite/CTX damage in <i>E. coli</i>.

<p>Peptidoglycan integrity (stability) is affected by CTX (1), favoring tellurite entry (2). Tellurite/CTX administration generates global transcriptional changes on different stress response pathways, transport, [Fe-S] clusters assembly, protein folding and different oxidative stress regulators (3). Finally, CTX and tellurite generate hydroxyl radical and superoxide respectively, damaging DNA, proteins and most probably other macromolecules.</p

Extracellular tellurite concentration in culture supernatants.

<p>Tellurite concentration was determined in supernatants of <i>E. coli</i> cultures that had been exposed to tellurite (20 µg ml⁻¹) in the absence (control) or presence of the indicated CTX concentrations. Values represent the average of 3 independent experiments. Statistical significance was determined using t-test. (**) p<0.01.</p

Tellurite-mediated antibiotic-potentiating effect in clinical isolates.

<p>Antibiotic susceptibility, in the absence or presence of the indicated tellurite concentrations, was assessed by growth inhibition zones (cm²) as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035452#s4" target="_blank">Methods</a>. Parentheses indicate per cent of susceptibility increase regarding the respective control.</p

Minimal tellurite concentration causing a cefotaxime-potentiating effect in <i>E. coli</i>.

<p>Inhibition growth zones were determined as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035452#s4" target="_blank">Methods</a> using LB plates amended with the indicated sub lethal tellurite concentrations (nM).</p

Tellurite-mediated antibiotic-potentiating effect in different bacteria.

<p>Antibiotic-mediated inhibition growth zones were determined for <i>E. coli</i> (A), <i>P. aeruginosa</i> (B) and <i>S. aureus</i> (C) grown in the absence (white bars) or presence of the indicated tellurite (T) concentrations as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035452#s4" target="_blank">Methods</a>. Values represent the average of at least 4 independent trials and significance was determined using t-test analysis (p<0.05). Significance values are (*) p<0.05, (**) p<0.01 and (***) p<0.001.</p

Cefotaxime and potassium tellurite acts synergistically in <i>E. coli</i>.

<p>Growth curves (left panels) and cell viability (right panels) were determined at the indicated time intervals for <i>E. coli</i> exposed to 0.065 (A, sublethal), 0.13 (B, MIC) and 0.5 µg/ml (C, lethal) CTX in the absence or presence of 200 nM tellurite. Controls contained no tellurite or cefotaxime. Data represent the mean of at least 3 independent trials. Refer to inset in panel A for symbol meaning.</p