IPA-3: An Inhibitor of Diadenylate Cyclase of Streptococcus suis with Potent Antimicrobial Activity
Antimicrobial resistance (AMR) poses a huge threat to public health. The development of novel antibiotics is an effective strategy to tackle AMR. Cyclic diadenylate monophosphate (c-di-AMP) has recently been identified as an essential signal molecule for some important bacterial pathogens involved i...
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Published in | Antibiotics (Basel) Vol. 11; no. 3; p. 418 |
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Abstract | Antimicrobial resistance (AMR) poses a huge threat to public health. The development of novel antibiotics is an effective strategy to tackle AMR. Cyclic diadenylate monophosphate (c-di-AMP) has recently been identified as an essential signal molecule for some important bacterial pathogens involved in various bacterial physiological processes, leading to its synthase diadenylate cyclase becoming an attractive antimicrobial drug target. In this study, based on the enzymatic activity of diadenylate cyclase of Streptococcus suis (ssDacA), we established a high-throughput method of screening for ssDacA inhibitors. Primary screening with a compound library containing 1133 compounds identified IPA-3 (2,2′-dihydroxy-1,1′-dinapthyldisulfide) as an ssDacA inhibitor. High-performance liquid chromatography (HPLC) analysis further indicated that IPA-3 could inhibit the production of c-di-AMP by ssDacA in vitro in a dose-dependent manner. Notably, it was demonstrated that IPA-3 could significantly inhibit the growth of several Gram-positive bacteria which harbor an essential diadenylate cyclase but not E. coli, which is devoid of the enzyme, or Streptococcus mutans, in which the diadenylate cyclase is not essential. Additionally, the binding site in ssDacA for IPA-3 was predicted by molecular docking, and contains residues that are relatively conserved in diadenylate cyclase of Gram-positive bacteria. Collectively, our results illustrate the feasibility of ssDacA as an antimicrobial target and consider IPA-3 as a promising starting point for the development of a novel antibacterial. |
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AbstractList | Antimicrobial resistance (AMR) poses a huge threat to public health. The development of novel antibiotics is an effective strategy to tackle AMR. Cyclic diadenylate monophosphate (c-di-AMP) has recently been identified as an essential signal molecule for some important bacterial pathogens involved in various bacterial physiological processes, leading to its synthase diadenylate cyclase becoming an attractive antimicrobial drug target. In this study, based on the enzymatic activity of diadenylate cyclase of Streptococcus suis (ssDacA), we established a high-throughput method of screening for ssDacA inhibitors. Primary screening with a compound library containing 1133 compounds identified IPA-3 (2,2'-dihydroxy-1,1'-dinapthyldisulfide) as an ssDacA inhibitor. High-performance liquid chromatography (HPLC) analysis further indicated that IPA-3 could inhibit the production of c-di-AMP by ssDacA in vitro in a dose-dependent manner. Notably, it was demonstrated that IPA-3 could significantly inhibit the growth of several Gram-positive bacteria which harbor an essential diadenylate cyclase but not E. coli, which is devoid of the enzyme, or Streptococcus mutans, in which the diadenylate cyclase is not essential. Additionally, the binding site in ssDacA for IPA-3 was predicted by molecular docking, and contains residues that are relatively conserved in diadenylate cyclase of Gram-positive bacteria. Collectively, our results illustrate the feasibility of ssDacA as an antimicrobial target and consider IPA-3 as a promising starting point for the development of a novel antibacterial.Antimicrobial resistance (AMR) poses a huge threat to public health. The development of novel antibiotics is an effective strategy to tackle AMR. Cyclic diadenylate monophosphate (c-di-AMP) has recently been identified as an essential signal molecule for some important bacterial pathogens involved in various bacterial physiological processes, leading to its synthase diadenylate cyclase becoming an attractive antimicrobial drug target. In this study, based on the enzymatic activity of diadenylate cyclase of Streptococcus suis (ssDacA), we established a high-throughput method of screening for ssDacA inhibitors. Primary screening with a compound library containing 1133 compounds identified IPA-3 (2,2'-dihydroxy-1,1'-dinapthyldisulfide) as an ssDacA inhibitor. High-performance liquid chromatography (HPLC) analysis further indicated that IPA-3 could inhibit the production of c-di-AMP by ssDacA in vitro in a dose-dependent manner. Notably, it was demonstrated that IPA-3 could significantly inhibit the growth of several Gram-positive bacteria which harbor an essential diadenylate cyclase but not E. coli, which is devoid of the enzyme, or Streptococcus mutans, in which the diadenylate cyclase is not essential. Additionally, the binding site in ssDacA for IPA-3 was predicted by molecular docking, and contains residues that are relatively conserved in diadenylate cyclase of Gram-positive bacteria. Collectively, our results illustrate the feasibility of ssDacA as an antimicrobial target and consider IPA-3 as a promising starting point for the development of a novel antibacterial. Antimicrobial resistance (AMR) poses a huge threat to public health. The development of novel antibiotics is an effective strategy to tackle AMR. Cyclic diadenylate monophosphate (c-di-AMP) has recently been identified as an essential signal molecule for some important bacterial pathogens involved in various bacterial physiological processes, leading to its synthase diadenylate cyclase becoming an attractive antimicrobial drug target. In this study, based on the enzymatic activity of diadenylate cyclase of Streptococcus suis (ssDacA), we established a high-throughput method of screening for ssDacA inhibitors. Primary screening with a compound library containing 1133 compounds identified IPA-3 (2,2′-dihydroxy-1,1′-dinapthyldisulfide) as an ssDacA inhibitor. High-performance liquid chromatography (HPLC) analysis further indicated that IPA-3 could inhibit the production of c-di-AMP by ssDacA in vitro in a dose-dependent manner. Notably, it was demonstrated that IPA-3 could significantly inhibit the growth of several Gram-positive bacteria which harbor an essential diadenylate cyclase but not E. coli, which is devoid of the enzyme, or Streptococcus mutans, in which the diadenylate cyclase is not essential. Additionally, the binding site in ssDacA for IPA-3 was predicted by molecular docking, and contains residues that are relatively conserved in diadenylate cyclase of Gram-positive bacteria. Collectively, our results illustrate the feasibility of ssDacA as an antimicrobial target and consider IPA-3 as a promising starting point for the development of a novel antibacterial. Antimicrobial resistance (AMR) poses a huge threat to public health. The development of novel antibiotics is an effective strategy to tackle AMR. Cyclic diadenylate monophosphate (c-di-AMP) has recently been identified as an essential signal molecule for some important bacterial pathogens involved in various bacterial physiological processes, leading to its synthase diadenylate cyclase becoming an attractive antimicrobial drug target. In this study, based on the enzymatic activity of diadenylate cyclase of (ssDacA), we established a high-throughput method of screening for ssDacA inhibitors. Primary screening with a compound library containing 1133 compounds identified IPA-3 (2,2'-dihydroxy-1,1'-dinapthyldisulfide) as an ssDacA inhibitor. High-performance liquid chromatography (HPLC) analysis further indicated that IPA-3 could inhibit the production of c-di-AMP by ssDacA in a dose-dependent manner. Notably, it was demonstrated that IPA-3 could significantly inhibit the growth of several Gram-positive bacteria which harbor an essential diadenylate cyclase but not , which is devoid of the enzyme, or , in which the diadenylate cyclase is not essential. Additionally, the binding site in ssDacA for IPA-3 was predicted by molecular docking, and contains residues that are relatively conserved in diadenylate cyclase of Gram-positive bacteria. Collectively, our results illustrate the feasibility of ssDacA as an antimicrobial target and consider IPA-3 as a promising starting point for the development of a novel antibacterial. Antimicrobial resistance (AMR) poses a huge threat to public health. The development of novel antibiotics is an effective strategy to tackle AMR. Cyclic diadenylate monophosphate (c-di-AMP) has recently been identified as an essential signal molecule for some important bacterial pathogens involved in various bacterial physiological processes, leading to its synthase diadenylate cyclase becoming an attractive antimicrobial drug target. In this study, based on the enzymatic activity of diadenylate cyclase of Streptococcus suis (ssDacA), we established a high-throughput method of screening for ssDacA inhibitors. Primary screening with a compound library containing 1133 compounds identified IPA-3 (2,2′-dihydroxy-1,1′-dinapthyldisulfide) as an ssDacA inhibitor. High-performance liquid chromatography (HPLC) analysis further indicated that IPA-3 could inhibit the production of c-di-AMP by ssDacA in vitro in a dose-dependent manner. Notably, it was demonstrated that IPA-3 could significantly inhibit the growth of several Gram-positive bacteria which harbor an essential diadenylate cyclase but not E. coli , which is devoid of the enzyme, or Streptococcus mutans , in which the diadenylate cyclase is not essential. Additionally, the binding site in ssDacA for IPA-3 was predicted by molecular docking, and contains residues that are relatively conserved in diadenylate cyclase of Gram-positive bacteria. Collectively, our results illustrate the feasibility of ssDacA as an antimicrobial target and consider IPA-3 as a promising starting point for the development of a novel antibacterial. |
Author | Li, Haotian Zhou, Rui Li, Tingting Huang, Qi Li, Lu Qiu, Xiuxiu Ni, Minghui Zou, Wenjin Hu, Qiao Yao, Zhiming Fan, Jingyan |
AuthorAffiliation | 3 International Research Center for Animal Disease (Ministry of Science & Technology of China), Wuhan 430070, China 1 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; lht@webmail.hzau.edu.cn (H.L.); li.tingting@webmail.hzau.edu.cn (T.L.); zouwenjin@webmail.hzau.edu.cn (W.Z.); minghuini@webmail.hzau.edu.cn (M.N.); huqiao@webmail.hzau.edu.cn (Q.H.); xiuxiuq@webmail.hzau.edu.cn (X.Q.); yaozhiming@webmail.hzau.edu.cn (Z.Y.); fjy6168@webmail.hzau.edu.cn (J.F.); lilu@mail.hzau.edu.cn (L.L.) 2 Cooperative Innovation Center of Sustainable Pig Production, Wuhan 430070, China 4 The HZAU-HVSEN Institute, Wuhan 430042, China |
AuthorAffiliation_xml | – name: 4 The HZAU-HVSEN Institute, Wuhan 430042, China – name: 1 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; lht@webmail.hzau.edu.cn (H.L.); li.tingting@webmail.hzau.edu.cn (T.L.); zouwenjin@webmail.hzau.edu.cn (W.Z.); minghuini@webmail.hzau.edu.cn (M.N.); huqiao@webmail.hzau.edu.cn (Q.H.); xiuxiuq@webmail.hzau.edu.cn (X.Q.); yaozhiming@webmail.hzau.edu.cn (Z.Y.); fjy6168@webmail.hzau.edu.cn (J.F.); lilu@mail.hzau.edu.cn (L.L.) – name: 3 International Research Center for Animal Disease (Ministry of Science & Technology of China), Wuhan 430070, China – name: 2 Cooperative Innovation Center of Sustainable Pig Production, Wuhan 430070, China |
Author_xml | – sequence: 1 givenname: Haotian surname: Li fullname: Li, Haotian – sequence: 2 givenname: Tingting surname: Li fullname: Li, Tingting – sequence: 3 givenname: Wenjin surname: Zou fullname: Zou, Wenjin – sequence: 4 givenname: Minghui surname: Ni fullname: Ni, Minghui – sequence: 5 givenname: Qiao surname: Hu fullname: Hu, Qiao – sequence: 6 givenname: Xiuxiu surname: Qiu fullname: Qiu, Xiuxiu – sequence: 7 givenname: Zhiming surname: Yao fullname: Yao, Zhiming – sequence: 8 givenname: Jingyan surname: Fan fullname: Fan, Jingyan – sequence: 9 givenname: Lu surname: Li fullname: Li, Lu – sequence: 10 givenname: Qi surname: Huang fullname: Huang, Qi – sequence: 11 givenname: Rui orcidid: 0000-0002-7903-9965 surname: Zhou fullname: Zhou, Rui |
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CitedBy_id | crossref_primary_10_1016_j_tim_2024_08_006 crossref_primary_10_1093_femsml_uqad021 crossref_primary_10_1128_spectrum_02418_23 crossref_primary_10_1093_femsre_fuad025 |
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Keywords | antimicrobial diadenylate cyclase inhibitor Streptococcus suis high-throughput screening IPA-3 cyclic diadenylate monophosphate |
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SubjectTerms | Antibiotics antimicrobial Antimicrobial activity Antimicrobial agents Antimicrobial resistance Bacteria Binding sites Biofilms Chromatography cyclic diadenylate monophosphate diadenylate cyclase Drug resistance E coli Enzymatic activity Gram-positive bacteria Health risks High performance liquid chromatography high-throughput screening Homeostasis inhibitor Inhibitors IPA-3 Kinases Liquid chromatography Meningitis Molecular docking Physiology Proteins Public health Screening Streptococcus infections Streptococcus suis Therapeutic targets Virulence |
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Title | IPA-3: An Inhibitor of Diadenylate Cyclase of Streptococcus suis with Potent Antimicrobial Activity |
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