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2518. Lead optimization on 26-membered thiopeptide antibiotics and identification of pre-clinical candidates against Clostridioides difficile and Staphylococcus aureus for impetigo
Abstract Background Thiopeptides are structurally complex natural products that exert potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. However, there has not been any attempt to conduct extensive medicinal chemistry campaign on these natural pr...
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Published in: | Open forum infectious diseases 2023-11, Vol.10 (Supplement_2) |
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creator | Hwang, Hee-Jong Son, Young-Jin Kim, Dahyun Lee, Jusuk Shyaka, Clovis Kwak, Jin-Hwan Pai, Hyunjoo Rho, Mina Park, Jong-Hwan Kim, Young-Rok Jung, Sungji |
description | Abstract
Background
Thiopeptides are structurally complex natural products that exert potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. However, there has not been any attempt to conduct extensive medicinal chemistry campaign on these natural products, due to their chemical complexity. The advent of efficient syntheses of thiopeptides led us to identify promising pre-clinical candidates: AJ-024 against Clostridioides difficile and AJ-147 against Staphylococcus aureus for the indication of impetigo.
Methods
AJ-024 was screened against extensively classified C. difficile clinical isolates. Its time-kill kinetics and in vivo mouse efficacy were investigated against hypervirulent C. difficile ribotype 027. Metagenomic sequencing (16S rRNA) was performed to examine AJ-024's impact on gut microbiome.
Similarly, AJ-147 was screened against methicillin-resistant S. aureus clinical isolates. Its time-kill kinetics, as well as its in vivo SSTI model were investigated. Pro-inflammatory cytokines were measured.
Pharmacokinetic studies of these two agents, as well as their ADME properties and toxicity have also been investigated.
Results
AJ-024 has potent antibacterial activity, along with rapid bactericidal action against C. difficile ribotype 027 resulting in 99.99% reduction in 4X MIC in 3 hours. No recurrence was observed in the mouse in vivo model and this was corroborated by our 16S rRNA sequencing data. AJ-024 exerts minimal impact on beneficial gut-microbiome.
AJ-147 exhibited a potent antibacterial activity against mupirocin resistant S. aureus. In vivo efficacy in a SSTI model revealed that AJ-147 is x1,000 more active than mupirocin. AJ-147 downregulates pro-inflammatory cytokines, such as IL-1ß and IL-6, that might elicit beneficial host immune response.
Impact of AJ-024 on gut microbiome
Investigation of AJ-024's impact on gut microbiome through 16s rRNA sequencing
In vivo efficacy of AJ-147 in SSTI model
AJ-147 compares favorably to mupirocin and downregulates pro-inflammatory cytokines
Conclusion
Our medicinal chemistry campaign on thiopeptide antibiotics have led us to identify two preclinical candidates, AJ-024 and AJ-147. These two agents possess distinctive advantages compared to the first-line of treatments for each indication. Efforts are being directed to the completion of IND-enabling studies.
Disclosures
Hee-Jong Hwang, PhD, A&J Science: Stocks/Bonds|KHIDI: Grant/Research Support Young-Jin S |
doi_str_mv | 10.1093/ofid/ofad500.2136 |
format | article |
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Background
Thiopeptides are structurally complex natural products that exert potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. However, there has not been any attempt to conduct extensive medicinal chemistry campaign on these natural products, due to their chemical complexity. The advent of efficient syntheses of thiopeptides led us to identify promising pre-clinical candidates: AJ-024 against Clostridioides difficile and AJ-147 against Staphylococcus aureus for the indication of impetigo.
Methods
AJ-024 was screened against extensively classified C. difficile clinical isolates. Its time-kill kinetics and in vivo mouse efficacy were investigated against hypervirulent C. difficile ribotype 027. Metagenomic sequencing (16S rRNA) was performed to examine AJ-024's impact on gut microbiome.
Similarly, AJ-147 was screened against methicillin-resistant S. aureus clinical isolates. Its time-kill kinetics, as well as its in vivo SSTI model were investigated. Pro-inflammatory cytokines were measured.
Pharmacokinetic studies of these two agents, as well as their ADME properties and toxicity have also been investigated.
Results
AJ-024 has potent antibacterial activity, along with rapid bactericidal action against C. difficile ribotype 027 resulting in 99.99% reduction in 4X MIC in 3 hours. No recurrence was observed in the mouse in vivo model and this was corroborated by our 16S rRNA sequencing data. AJ-024 exerts minimal impact on beneficial gut-microbiome.
AJ-147 exhibited a potent antibacterial activity against mupirocin resistant S. aureus. In vivo efficacy in a SSTI model revealed that AJ-147 is x1,000 more active than mupirocin. AJ-147 downregulates pro-inflammatory cytokines, such as IL-1ß and IL-6, that might elicit beneficial host immune response.
Impact of AJ-024 on gut microbiome
Investigation of AJ-024's impact on gut microbiome through 16s rRNA sequencing
In vivo efficacy of AJ-147 in SSTI model
AJ-147 compares favorably to mupirocin and downregulates pro-inflammatory cytokines
Conclusion
Our medicinal chemistry campaign on thiopeptide antibiotics have led us to identify two preclinical candidates, AJ-024 and AJ-147. These two agents possess distinctive advantages compared to the first-line of treatments for each indication. Efforts are being directed to the completion of IND-enabling studies.
Disclosures
Hee-Jong Hwang, PhD, A&J Science: Stocks/Bonds|KHIDI: Grant/Research Support Young-Jin Son, A&J Science: Employee of A&J Science|A&J Science: Ownership Interest|KHIDI: Grant/Research Support Dahyun Kim, n/a, A&J Science: Employee of A&J Science Jusuk Lee, Ph.D., A&J Science: Employee of A&J Science Clovis Shyaka, n/a, A&J Science: Employee of A&J Science]]></description><identifier>ISSN: 2328-8957</identifier><identifier>EISSN: 2328-8957</identifier><identifier>DOI: 10.1093/ofid/ofad500.2136</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><ispartof>Open forum infectious diseases, 2023-11, Vol.10 (Supplement_2)</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Hwang, Hee-Jong</creatorcontrib><creatorcontrib>Son, Young-Jin</creatorcontrib><creatorcontrib>Kim, Dahyun</creatorcontrib><creatorcontrib>Lee, Jusuk</creatorcontrib><creatorcontrib>Shyaka, Clovis</creatorcontrib><creatorcontrib>Kwak, Jin-Hwan</creatorcontrib><creatorcontrib>Pai, Hyunjoo</creatorcontrib><creatorcontrib>Rho, Mina</creatorcontrib><creatorcontrib>Park, Jong-Hwan</creatorcontrib><creatorcontrib>Kim, Young-Rok</creatorcontrib><creatorcontrib>Jung, Sungji</creatorcontrib><title>2518. Lead optimization on 26-membered thiopeptide antibiotics and identification of pre-clinical candidates against Clostridioides difficile and Staphylococcus aureus for impetigo</title><title>Open forum infectious diseases</title><description><![CDATA[Abstract
Background
Thiopeptides are structurally complex natural products that exert potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. However, there has not been any attempt to conduct extensive medicinal chemistry campaign on these natural products, due to their chemical complexity. The advent of efficient syntheses of thiopeptides led us to identify promising pre-clinical candidates: AJ-024 against Clostridioides difficile and AJ-147 against Staphylococcus aureus for the indication of impetigo.
Methods
AJ-024 was screened against extensively classified C. difficile clinical isolates. Its time-kill kinetics and in vivo mouse efficacy were investigated against hypervirulent C. difficile ribotype 027. Metagenomic sequencing (16S rRNA) was performed to examine AJ-024's impact on gut microbiome.
Similarly, AJ-147 was screened against methicillin-resistant S. aureus clinical isolates. Its time-kill kinetics, as well as its in vivo SSTI model were investigated. Pro-inflammatory cytokines were measured.
Pharmacokinetic studies of these two agents, as well as their ADME properties and toxicity have also been investigated.
Results
AJ-024 has potent antibacterial activity, along with rapid bactericidal action against C. difficile ribotype 027 resulting in 99.99% reduction in 4X MIC in 3 hours. No recurrence was observed in the mouse in vivo model and this was corroborated by our 16S rRNA sequencing data. AJ-024 exerts minimal impact on beneficial gut-microbiome.
AJ-147 exhibited a potent antibacterial activity against mupirocin resistant S. aureus. In vivo efficacy in a SSTI model revealed that AJ-147 is x1,000 more active than mupirocin. AJ-147 downregulates pro-inflammatory cytokines, such as IL-1ß and IL-6, that might elicit beneficial host immune response.
Impact of AJ-024 on gut microbiome
Investigation of AJ-024's impact on gut microbiome through 16s rRNA sequencing
In vivo efficacy of AJ-147 in SSTI model
AJ-147 compares favorably to mupirocin and downregulates pro-inflammatory cytokines
Conclusion
Our medicinal chemistry campaign on thiopeptide antibiotics have led us to identify two preclinical candidates, AJ-024 and AJ-147. These two agents possess distinctive advantages compared to the first-line of treatments for each indication. Efforts are being directed to the completion of IND-enabling studies.
Disclosures
Hee-Jong Hwang, PhD, A&J Science: Stocks/Bonds|KHIDI: Grant/Research Support Young-Jin Son, A&J Science: Employee of A&J Science|A&J Science: Ownership Interest|KHIDI: Grant/Research Support Dahyun Kim, n/a, A&J Science: Employee of A&J Science Jusuk Lee, Ph.D., A&J Science: Employee of A&J Science Clovis Shyaka, n/a, A&J Science: Employee of A&J Science]]></description><issn>2328-8957</issn><issn>2328-8957</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><recordid>eNqNkNtKAzEQhoMoWLQP4F0ewK05bPZwKcUTFLxQr5dsMmlHdpslSS_qc_mAprYXXgrDzPDzf8PwE3LD2YKzVt55hzY3bRVjC8FldUZmQoqmaFpVn__ZL8k8xk_GGOdMsbqdkW-heLOgK9CW-inhiF86od_SXKIqRhh7CGBp2qCfIBssUL1N2KNPaGLeLc1aVhyaE-noFKAwA26zNFCTPWh1guxea9zGRJeDjymgRZ_ZSC26TOMAv-fekp42-8Ebb8wuM7sAeTgfKI4TJFz7a3Lh9BBhfppX5OPx4X35XKxen16W96vCcJGfB1W3AlRbaVZqY5WEqmVl3_eSl4IZrUDIvgQJteWNqV0tS2FM6YQDKK0s5RXhx7sm-BgDuG4KOOqw7zjrDsl3h-S7U_LdIfnM3B4Zv5v-Yf8BWweMHA</recordid><startdate>20231127</startdate><enddate>20231127</enddate><creator>Hwang, Hee-Jong</creator><creator>Son, Young-Jin</creator><creator>Kim, Dahyun</creator><creator>Lee, Jusuk</creator><creator>Shyaka, Clovis</creator><creator>Kwak, Jin-Hwan</creator><creator>Pai, Hyunjoo</creator><creator>Rho, Mina</creator><creator>Park, Jong-Hwan</creator><creator>Kim, Young-Rok</creator><creator>Jung, Sungji</creator><general>Oxford University Press</general><scope>TOX</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20231127</creationdate><title>2518. Lead optimization on 26-membered thiopeptide antibiotics and identification of pre-clinical candidates against Clostridioides difficile and Staphylococcus aureus for impetigo</title><author>Hwang, Hee-Jong ; Son, Young-Jin ; Kim, Dahyun ; Lee, Jusuk ; Shyaka, Clovis ; Kwak, Jin-Hwan ; Pai, Hyunjoo ; Rho, Mina ; Park, Jong-Hwan ; Kim, Young-Rok ; Jung, Sungji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1226-e5792e596a04acd53e6904bbb31420ca5e23b4e3e7d18c7f7342cc4f2fee4d343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hwang, Hee-Jong</creatorcontrib><creatorcontrib>Son, Young-Jin</creatorcontrib><creatorcontrib>Kim, Dahyun</creatorcontrib><creatorcontrib>Lee, Jusuk</creatorcontrib><creatorcontrib>Shyaka, Clovis</creatorcontrib><creatorcontrib>Kwak, Jin-Hwan</creatorcontrib><creatorcontrib>Pai, Hyunjoo</creatorcontrib><creatorcontrib>Rho, Mina</creatorcontrib><creatorcontrib>Park, Jong-Hwan</creatorcontrib><creatorcontrib>Kim, Young-Rok</creatorcontrib><creatorcontrib>Jung, Sungji</creatorcontrib><collection>Open Access: Oxford University Press Open Journals</collection><collection>CrossRef</collection><jtitle>Open forum infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hwang, Hee-Jong</au><au>Son, Young-Jin</au><au>Kim, Dahyun</au><au>Lee, Jusuk</au><au>Shyaka, Clovis</au><au>Kwak, Jin-Hwan</au><au>Pai, Hyunjoo</au><au>Rho, Mina</au><au>Park, Jong-Hwan</au><au>Kim, Young-Rok</au><au>Jung, Sungji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2518. Lead optimization on 26-membered thiopeptide antibiotics and identification of pre-clinical candidates against Clostridioides difficile and Staphylococcus aureus for impetigo</atitle><jtitle>Open forum infectious diseases</jtitle><date>2023-11-27</date><risdate>2023</risdate><volume>10</volume><issue>Supplement_2</issue><issn>2328-8957</issn><eissn>2328-8957</eissn><abstract><![CDATA[Abstract
Background
Thiopeptides are structurally complex natural products that exert potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. However, there has not been any attempt to conduct extensive medicinal chemistry campaign on these natural products, due to their chemical complexity. The advent of efficient syntheses of thiopeptides led us to identify promising pre-clinical candidates: AJ-024 against Clostridioides difficile and AJ-147 against Staphylococcus aureus for the indication of impetigo.
Methods
AJ-024 was screened against extensively classified C. difficile clinical isolates. Its time-kill kinetics and in vivo mouse efficacy were investigated against hypervirulent C. difficile ribotype 027. Metagenomic sequencing (16S rRNA) was performed to examine AJ-024's impact on gut microbiome.
Similarly, AJ-147 was screened against methicillin-resistant S. aureus clinical isolates. Its time-kill kinetics, as well as its in vivo SSTI model were investigated. Pro-inflammatory cytokines were measured.
Pharmacokinetic studies of these two agents, as well as their ADME properties and toxicity have also been investigated.
Results
AJ-024 has potent antibacterial activity, along with rapid bactericidal action against C. difficile ribotype 027 resulting in 99.99% reduction in 4X MIC in 3 hours. No recurrence was observed in the mouse in vivo model and this was corroborated by our 16S rRNA sequencing data. AJ-024 exerts minimal impact on beneficial gut-microbiome.
AJ-147 exhibited a potent antibacterial activity against mupirocin resistant S. aureus. In vivo efficacy in a SSTI model revealed that AJ-147 is x1,000 more active than mupirocin. AJ-147 downregulates pro-inflammatory cytokines, such as IL-1ß and IL-6, that might elicit beneficial host immune response.
Impact of AJ-024 on gut microbiome
Investigation of AJ-024's impact on gut microbiome through 16s rRNA sequencing
In vivo efficacy of AJ-147 in SSTI model
AJ-147 compares favorably to mupirocin and downregulates pro-inflammatory cytokines
Conclusion
Our medicinal chemistry campaign on thiopeptide antibiotics have led us to identify two preclinical candidates, AJ-024 and AJ-147. These two agents possess distinctive advantages compared to the first-line of treatments for each indication. Efforts are being directed to the completion of IND-enabling studies.
Disclosures
Hee-Jong Hwang, PhD, A&J Science: Stocks/Bonds|KHIDI: Grant/Research Support Young-Jin Son, A&J Science: Employee of A&J Science|A&J Science: Ownership Interest|KHIDI: Grant/Research Support Dahyun Kim, n/a, A&J Science: Employee of A&J Science Jusuk Lee, Ph.D., A&J Science: Employee of A&J Science Clovis Shyaka, n/a, A&J Science: Employee of A&J Science]]></abstract><cop>US</cop><pub>Oxford University Press</pub><doi>10.1093/ofid/ofad500.2136</doi><oa>free_for_read</oa></addata></record> |
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title | 2518. Lead optimization on 26-membered thiopeptide antibiotics and identification of pre-clinical candidates against Clostridioides difficile and Staphylococcus aureus for impetigo |
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