Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

Crane, John K.; Broome, Jackie E; Reddinger, Ryan M.; Werth, Benjamin B

doi:10.1186/1471-2180-14-145

Cited by 30 publications

(30 citation statements)

References 79 publications

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“…As we began to appreciate that zinc inhibited the SOS response [4], we hypothesized that zinc’s effects might extend well beyond STEC and Stx and extend to other E . coli strains and other bacteria as well.…”

Section: Discussionmentioning

confidence: 99%

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

et al. 2017

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Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

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Section: Discussionmentioning

confidence: 99%

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

et al. 2017

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“…Stx is not exported by any bacterial secretory machinery [ 13 , 14 , 15 , 16 ] and release of this exotoxin from the bacteria depends on phage genes that cause bacterial lysis [ 17 , 18 ]. Therefore, in the case of Stx-encoding prophages, induction concomitantly allows expression of the stx genes [ 19 , 20 ] and those needed for its release.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms that Determine the Differential Stability of Stx+ and Stx− Lysogens

Colon

Chakraborty

Pevzner

et al. 2016

Toxins

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Phages 933W, BAA2326, 434, and λ are evolutionarily-related temperate lambdoid phages that infect Escherichia coli. Although these are highly-similar phages, BAA2326 and 933W naturally encode Shiga toxin 2 (Stx+), but phage 434 and λ do not (Stx−). Previous reports suggest that the 933W Stx+ prophage forms less stable lysogens in E. coli than does the Stx− prophages λ, P22, and 434. The higher spontaneous induction frequency of the Stx+ prophage may be correlated with both virulence and dispersion of the Stx2-encoding phage. Here, we examined the hypothesis that lysogen instability is a common feature of Stx+ prophages. We found in both the absence and presence of prophage inducers (DNA damaging agents, salts), the Stx+ prophages induce at higher frequencies than do Stx− prophages. The observed instability of Stx+ prophages does not appear to be the result of any differences in phage development properties between Stx+ and Stx− phages. Our results indicate that differential stability of Stx+ and Stx− prophages results from both RecA-dependent and RecA-independent effects on the intracellular concentration of the respective cI repressors.

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“…Although Zn is an essential micronutrient for bacteria, it is toxic at high concentrations [ 23 ]. Zn plays a protective role against infection by other pathogens, such as shiga-toxigenic Escherichia coli [ 24 ] and Trypanosoma evansi [ 25 ]. A bacteriostatic effect of Zn was demonstrated using in vitro bacterial growth assays.…”

Section: Discussionmentioning

confidence: 99%

Combination of Zinc and All-Trans Retinoic Acid Promotes Protection against Listeria monocytogenes Infection

et al. 2015

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Zinc (Zn) is the second most abundant transition metal after iron. It plays a vital role in living organisms and affects multiple aspects of the immune system. All-trans retinoic acid (atRA) is an isomeric form of the vitamin A or retinol. It possesses the greatest biological activity of Vitamin A. Vitamin A and related retinoids influence many aspects of immunity. In this study, we demonstrated that treatment with a combination of Zn and atRA contributes to host resistance against infection by Listeria monocytogenes. Pretreatment with Zn and atRA enhanced resistance against L. monocytogenes infection in mice and treatment with both Zn and atRA showed a higher protective effect than treatment with either alone. Supplementation with Zn, atRA or their combination decreased the number of L. monocytogenes present in target organs. In vitro, supplementation increased the bacterial uptake by macrophage cells and reduced the replication of L. monocytogenes. Our results suggest that the combination of Zn and atRA has a great bacteriostatic impact on L. monocytogenes and its infection.

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Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

Cited by 30 publications

References 79 publications

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

Mechanisms that Determine the Differential Stability of Stx+ and Stx− Lysogens

Combination of Zinc and All-Trans Retinoic Acid Promotes Protection against Listeria monocytogenes Infection

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