DNA, Cell Wall and General Oxidative Damage Underlie the Tellurite/Cefotaxime Synergistic Effect in Escherichia coli

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.

Exposure to sub-inhibitory concentrations of cefotaxime enhances the systemic colonization of Salmonella Typhimurium in BALB/c mice

“…As mentioned, controversial evidence has been shown indicating that bactericidal antibiotics owe part of their toxicity to oxidative stress establishment [ 33 , 34 ]. Notably, the colonization phenotype is not a consequence of bacterial adaptation to the oxidative damage generated by the antibiotic ( figure 4 ), as has been shown previously [ 32 ].…”

“…On the other hand, it has been described that bactericidal antibiotics, and specifically CTX, generate oxidative stress [ 32 – 34 ]. However, this concept remains controversial as many publications have challenged the original findings [ 35 , 36 ].…”

Unraveling the Physiological Complexities of Antibiotic Lethality

“…bacteria, including resistant strains, persisters, and biofilms. With respect to tellurite, two recent studies by Molina-Quiroz et al (140,141) found that nonlethal levels of this tellurium oxyanion can enhance the lethality of several antibiotics, including ampicillin and gentamicin. They demonstrated that a ROS component is involved in the lethal synergy of cefotaxime (a cephalosporin β-lactam) with tellurite by showing that the combination treatment results in oxidative damage to DNA and proteins (141).…”

Cyclic AMP Regulates Bacterial Persistence through Repression of the Oxidative Stress Response and SOS-Dependent DNA Repair in Uropathogenic Escherichia coli

“…UPEC cultures were grown as described above and challenged for 1 h with ampicillin at 1,250 µg/ml or with 50 µM FeSO 4 and 10 mM H 2 O 2 to generate hydroxyl radicals by the Fenton reaction (positive control) as previously described ( 32 ). Total ROS and hydroxyl radical levels were assessed with H 2 DCFDA and HPF, respectively, as previously described ( 14 , 53 ). Fluorescence of cultures was determined in a Synergy H1 microplate reader (BioTek) fluorimeter.…”