| 英文摘要 | Antimicrobial resistance (AMR) is the silent pandemic. It has been steadily increasing over many years and threatens to halt the practice of modern medicine. By 2050, the annual number of worldwide deaths due to AMR will be ∼10 million, with an estimated economic impact of 100 trillion USD ([ 1 ][1]). The World Health Organization, United Nations, and governments worldwide agree that plans for surveillance, stewardship, and innovation must be implemented to avoid a future global catastrophe ([ 2 ][2], [ 3 ][3]). An integral part of prolonging the usefulness of antibiotics will be to identify new ways to combat antibiotic-resistant bacterial infections. On page 1169 of this issue, Shatalin et al. ([ 4 ][4]) provide hope by presenting an approach that makes bacteria more susceptible to antibiotics. It hinges on crippling a universal bacterial defense mechanism whereby hydrogen sulfide (H2S) protects bacteria from the toxic effects of reactive oxygen species (ROS). Once disabled as such, bacteria become more susceptible to antibiotics.
The ability of a bacterium to withstand the activity of antibiotics is attributed to several factors ([ 5 ][5]). The most intuitive concept is mutation and selection. Bacteria have built-in stress response mechanisms, most notably the increased expression of error-prone DNA polymerases furthers the likelihood of generating a mutation that will allow the bacterium to survive exposure to antimicrobial agents. However, AMR is not all about the acquisition of mutations. Because bacteria in nature must establish a niche, many antimicrobial compounds are produced by bacteria to outcompete other microbes in the ecosystem. Producers must protect themselves from the toxic effects of those antimicrobial compounds through various resistance mechanisms encoded in their genomes. These resistance mechanisms can be transferred to other bacteria through transformation (bacteria take up exogenous genetic material from the environment), transduction (viruses pass genetic material to bacteria), or conjugation (bacteria transfer genetic material between each other).
The glory days of antibiotic discovery occurred between 1940 and 1960. Initial screens uncovered compounds that affected what are now known as the standard targets of antibiotics (bacterial cell wall, bacterial ribosome). Unfortunately, expansion of that list of initial compounds and targets has slowed to the point where only one new target [adenosine 5′-triphosphate synthesis; ([ 6 ][6])] has been identified in the last several decades.
The past 15 years have seen exciting, albeit somewhat controversial, updates to our fundamental understanding of the mechanisms by which antibiotics kill bacteria ([ 7 ][7], [ 8 ][8]). The production of lethal ROS by bacteria through Fenton chemistry was proposed to be a common pathway to cell death upon exposure to bactericidal antibiotics (an agent that kills bacteria as opposed to bacteriostatic antibiotics, which inhibit bacterial growth) ([ 9 ][9]). This led to the hypothesis that impairing the bacterial antioxidant defenses that detoxify ROS will bolster bacterial susceptibility to antibiotics. For instance, bacterial superoxide dismutase, which breaks down ROS, was reported as critical for antibiotic tolerance in Pseudomonas aeruginosa ([ 10 ][10]).
Shatalin et al. focused on the role of another protective mechanism against oxidative stress: H2S production. It was previously shown that endogenous H2S protects bacterial cells from oxidative stress caused by exposure to bactericidal antibiotics ([ 11 ][11]). Impairing H2S production and, consequently, the downstream oxidative stress response, results in increased susceptibility to antibiotics. The proposed mechanism for this protection is through the sequestration of iron and subsequent prevention of the Fenton reaction ([ 12 ][12]).
Shatalin et al. use mutants of Staphylococcus aureus and P. aeruginosa , to establish that cystathionine-γ-lyase (CSE) is the main source of H2S. These observations provided the rationale for identifying small-molecule inhibitors of bacterial CSE. Using x-ray crystallographic structures of human CSE, CSE-like enzymes, and the structure of S. aureus CSE, the authors identified a possible site for the binding of allosteric inhibitors that have much less affinity for human CSE. Shatalin et al. used a structure-based virtual screening approach to screen through ∼3.2 million commercially available small molecules and identified three compounds with a marked inhibitory effect on H2S production in S. aureus and P. aeruginosa .
Shatalin et al. demonstrated that all three compounds increased the sensitivity of different S. aureus and P. aeruginosa strains to bactericidal, but not bacteriostatic, antibiotics from several different classes. This potentiation did not occur when an iron chelator was included in the assay, supporting the model that cell death occurs through the Fenton reaction. One of the compounds improved the survival outcomes of mice infected with either S. aureus or P. aeruginosa when it was combined with the aminoglycoside antibiotic gentamicin.
The findings of Shatalin et al. bring us one step closer to therapeutically targeting H2S production to bolster antibiotic activity. Given that H2S-producing enzymes are present in most bacteria, inhibition of bacterial H2S production may be a true game changer.
1. [↵][13]1. J. O'Neill
, “Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations” (2014); .
2. [↵][14]World Health Organization, “No Time to Wait: Securing the Future from Drug-Resistant Infections” (2019); [www.who.int/antimicrobial-resistance/interagency-coordination-group/final-report/en/][15].
3. [↵][16]Government of Canada, “Tackling antimicrobial resistance and antimicrobial use: A Pan Canadian Framework for Action” (2017); [www.canada.ca/en/health-canada/services/publications/drugs-health-products/tackling-antimicrobial-resistance-use-pan-canadian-framework-action.html][17].
4. [↵][18]1. K. Shatalin et al
., Science 372, 1169 (2021).
[OpenUrl][19][Abstract/FREE Full Text][20]
5. [↵][21]1. J. M. A. Blair et al
., Nat. Rev. Microbiol. 13, 42 (2015).
[OpenUrl][22][CrossRef][23][PubMed][24]
6. [↵][25]1. M. I. Hutchings,
2. A. W. Truman,
3. B. Wilkinson
, Curr. Opin. Microbiol. 51, 72 (2019).
[OpenUrl][26][CrossRef][27][PubMed][28]
7. [↵][29]1. H. Van Acker,
2. T. Coenye
, Trends Microbiol. 25, 456 (2017).
[OpenUrl][30][CrossRef][31][PubMed][32]
8. [↵][33]1. D. J. Dwyer,
2. J. J. Collins,
3. G. C. Walker
, Annu. Rev. Pharmacol. Toxicol. 55, 313 (2015).
[OpenUrl][34][CrossRef][35][PubMed][36]
9. [↵][37]1. M. A. Kohanski et al
., Cell 130, 797 (2007).
[OpenUrl][38][CrossRef][39][PubMed][40][Web of Science][41]
10. [↵][42]1. D. Martins et al
., Proc. Natl. Acad. Sci. U.S.A. 115, 9797 (2018).
[OpenUrl][43][Abstract/FREE Full Text][44]
11. [↵][45]1. K. Shatalin et al
., Science 334, 986 (2011).
[OpenUrl][46][Abstract/FREE Full Text][47]
12. [↵][48]1. A. Mironov et al
., Proc. Natl. Acad. Sci. U.S.A. 114, 6022 (2017).
[OpenUrl][49][Abstract/FREE Full Text][50]
Acknowledgments: I thank C. Hall, M. Puri, and M. Downey for helpful comments.
[1]: #ref-1
[2]: #ref-2
[3]: #ref-3
[4]: #ref-4
[5]: #ref-5
[6]: #ref-6
[7]: #ref-7
[8]: #ref-8
[9]: #ref-9
[10]: #ref-10
[11]: #ref-11
[12]: #ref-12
[13]: #xref-ref-1-1 "View reference 1 in text"
[14]: #xref-ref-2-1 "View reference 2 in text"
[15]: http://www.who.int/antimicrobial-resistance/interagency-coordination-group/final-report/en/
[16]: #xref-ref-3-1 "View reference 3 in text"
[17]: http://www.canada.ca/en/health-canada/services/publications/drugs-health-products/tackling-antimicrobial-resistance-use-pan-canadian-framework-action.html
[18]: #xref-ref-4-1 "View reference 4 in text"
[19]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DShatalin%26rft.auinit1%253DK.%26rft.volume%253D372%26rft.issue%253D6547%26rft.spage%253D1169%26rft.epage%253D1175%26rft.atitle%253DInhibitors%2Bof%2Bbacterial%2BH2S%2Bbiogenesis%2Btargeting%2Bantibiotic%2Bresistance%2Band%2Btolerance%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.abd8377%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[20]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIzNzIvNjU0Ny8xMTY5IjtzOjQ6ImF0b20iO3M6MjM6Ii9zY2kvMzcyLzY1NDcvMTE1My5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=
[21]: #xref-ref-5-1 "View reference 5 in text"
[22]: {openurl}?query=rft.jtitle%253DNat.%2BRev.%2BMicrobiol.%26rft.volume%253D13%26rft.spage%253D42%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnrmicro3380%26rft_id%253Dinfo%253Apmid%252F25435309%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[23]: /lookup/external-ref?access_num=10.1038/nrmicro3380&link_type=DOI
[24]: /lookup/external-ref?access_num=25435309&link_type=MED&atom=%2Fsci%2F372%2F6547%2F1153.atom
[25]: #xref-ref-6-1 "View reference 6 in text"
[26]: {openurl}?query=rft.jtitle%253DCurr.%2BOpin.%2BMicrobiol.%26rft.volume%253D51%26rft.spage%253D72%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.mib.2019.10.008%26rft_id%253Dinfo%253Apmid%252F31733401%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[27]: /lookup/external-ref?access_num=10.1016/j.mib.2019.10.008&link_type=DOI
[28]: /lookup/external-ref?access_num=31733401&link_type=MED&atom=%2Fsci%2F372%2F6547%2F1153.atom
[29]: #xref-ref-7-1 "View reference 7 in text"
[30]: {openurl}?query=rft.jtitle%253DTrends%2BMicrobiol.%26rft.volume%253D25%26rft.spage%253D456%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.tim.2016.12.008%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[31]: /lookup/external-ref?access_num=10.1016/j.tim.2016.12.008&link_type=DOI
[32]: /lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fsci%2F372%2F6547%2F1153.atom
[33]: #xref-ref-8-1 "View reference 8 in text"
[34]: {openurl}?query=rft.jtitle%253DAnnu.%2BRev.%2BPharmacol.%2BToxicol.%26rft.volume%253D55%26rft.spage%253D313%26rft_id%253Dinfo%253Adoi%252F10.1146%252Fannurev-pharmtox-010814-124712%26rft_id%253Dinfo%253Apmid%252F25251995%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[35]: /lookup/external-ref?access_num=10.1146/annurev-pharmtox-010814-124712&link_type=DOI
[36]: /lookup/external-ref?access_num=25251995&link_type=MED&atom=%2Fsci%2F372%2F6547%2F1153.atom
[37]: #xref-ref-9-1 "View reference 9 in text"
[38]: {openurl}?query=rft.jtitle%253DCell%26rft.stitle%253DCell%26rft.aulast%253DKohanski%26rft.auinit1%253DM.%2BA.%26rft.volume%253D130%26rft.issue%253D5%26rft.spage%253D797%26rft.epage%253D810%26rft.atitle%253DA%2Bcommon%2Bmechanism%2Bof%2Bcellular%2Bdeath%2Binduced%2Bby%2Bbactericidal%2Bantibiotics.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cell.2007.06.049%26rft_id%253Dinfo%253Apmid%252F17803904%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[39]: /lookup/external-ref?access_num=10.1016/j.cell.2007.06.049&link_type=DOI
[40]: /lookup/external-ref?access_num=17803904&link_type=MED&atom=%2Fsci%2F372%2F6547%2F1153.atom
[41]: /lookup/external-ref?access_num=000249581500013&link_type=ISI
[42]: #xref-ref-10-1 "View reference 10 in text"
[43]: {openurl}?query=rft.jtitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BU.S.A.%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.1804525115%26rft_id%253Dinfo%253Apmid%252F30201715%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[44]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMToiMTE1LzM5Lzk3OTciO3M6NDoiYXRvbSI7czoyMzoiL3NjaS8zNzIvNjU0Ny8xMTUzLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==
[45]: #xref-ref-11-1 "View reference 11 in text"
[46]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DShatalin%26rft.auinit1%253DK.%26rft.volume%253D334%26rft.issue%253D6058%26rft.spage%253D986%26rft.epage%253D990%26rft.atitle%253DH2S%253A%2BA%2BUniversal%2BDefense%2BAgainst%2BAntibiotics%2Bin%2BBacteria%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1209855%26rft_id%253Dinfo%253Apmid%252F22096201%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[47]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzMzQvNjA1OC85ODYiO3M6NDoiYXRvbSI7czoyMzoiL3NjaS8zNzIvNjU0Ny8xMTUzLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==
[48]: #xref-ref-12-1 "View reference 12 in text"
[49]: {openurl}?query=rft.jtitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BU.S.A.%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.1703576114%26rft_id%253Dinfo%253Apmid%252F28533366%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[50]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMToiMTE0LzIzLzYwMjIiO3M6NDoiYXRvbSI7czoyMzoiL3NjaS8zNzIvNjU0Ny8xMTUzLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== |
修改评论