Cell Host & Microbe sulfonamides in the treatment of Firmicutes bacterial infections can cause STING-mediated inflammatory responses

Editor | Xi The misuse of antibiotics and the emergence of drug-resistant bacteria have become major global public health problems
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While inhibiting the growth of microorganisms or directly killing microorganisms, antibiotics can affect the physiological activities of bacteria or change the cell structure, which may change the immune recognition of bacteria by host cells and the downstream inflammatory response [1]
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Cyclic dinucleotides produced by bacteria are important second messenger molecules that mediate host recognition of bacterial infection
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Among them, c-di-AMP (cyclic di-AMP) is widely present in Gram-positive bacteria and regulates bacterial central metabolism, cell osmotic pressure, cell wall structure and the virulence of pathogenic bacteria
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After bacterial infection of the host, c-di-AMP can be recognized and bound by the host STING (Stimulator of Interferon Genes) protein to activate the downstream immune response, resulting in Type I interferon and proinflammatory cytokines.
cytokine) generation [2]
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However, the complex relationship between antibiotic treatment, bacterial physiology, and host immune responses remains to be studied
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On April 18, 2022, the Woodward team of Washington University School of Medicine (first author Dr.
Qing Tang) published a research paper titled Thymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection in Cell Host & Microbe , the study found that sulfonamide antibiotics can promote the induction of type I interferon by Enterococcus faecalis, Listeria monocytogenes and Staphylococcus aureus after infection of macrophages
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The study further found that sulfonamide antibiotics blocked the regeneration pathway of folate required for thymidine biosynthesis, which ultimately led to higher concentrations of c-di-AMP in bacteria, which activated the STING pathway
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More importantly, sulfonamides are widely used to treat bacterial infections in cystic fibrosis patients
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Long-term use of this antibiotic results in the production of thymidine-dependent auxotrophic bacteria (also known as thymidine-dependent S.
aureus small colony variants, TD-SCVs), which are caused by genetic mutations that cause thymidylate synthase (Thymidylate synthase) , ThyA) loss-of-function and can only maintain DNA synthesis by uptake of thymidine from the environment
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At the same time, because TD-SCV no longer relies on folic acid to synthesize thymidine, they become resistant to sulfonamides, resulting in recurrent or long-term pulmonary infections that are difficult to clear [3]
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This study found that TD-SCV in the absence of thymidine produces high concentrations of c-di-AMP, activates the STING pathway, and promotes the production of pro-inflammatory cytokines and the enrichment of neutrophils in the lungs
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This study further sheds light on the underlying cause of TD-SCV-induced severe lung infection in cystic fibrosis patients, leading to decreased lung function
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In conclusion, this study demonstrates that blockade of thymidine metabolism in Firmicutes by sulfonamides leads to c-di-AMP-mediated activation of the STING pathway, revealing the effect of antibiotic treatment on the host's innate immune response
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Original link: https://authors.
elsevier.
com/c/1ex3Z6t8JEj9~n Plate maker: Eleven References 1.
Anderson, R.
, Tintinger, G.
, Cockeran, R.
, Potjo, M.
, and Feldman, C.
(2010).
Beneficial and harmful interactions of antibiotics with microbial pathogens and the host innate immune system.
Pharmaceuticals, 3(5):1694-1710.
doi: 10.
3390/ph3051694.
2.
Woodward, JJ, Lavarone, AT, and Portnoy, DA (2010).
C-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response.
Science.
328(5986):1703-5.
doi: 10.
1126/science.
1189801.
3.
Wolter, DJ, Onchiri, FM, Emerson, J.
, Precit, MR, Lee, M.
, McNamara, S.
, Nay, L.
, Blackledge, M.
, Uluer, A.
, Orenstein, DM, et al.
(2019).
Prevalence and clinical associations of Staphylococcus aureus small-colony variant respiratory infection in children with cystic fibrosis (SCVSA): a multicentre, observational study.
Lancet Respir.
Med.
7(12):1027-1038.
doi: 10.
1016/S2213-2600(19)30365-0.
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