Nimra Khalid, Nicole Adams, Federico Cunha, Aya C Taki, Thuy G Le, Jonathan B Baell, Henry S Heine, Robin B Gasser, Aria Eshraghi
{"title":"唑吩吡啶衍生物具有强效的弗朗西斯菌特异性抗菌活性,且对哺乳动物体外细胞无毒性。","authors":"Nimra Khalid, Nicole Adams, Federico Cunha, Aya C Taki, Thuy G Le, Jonathan B Baell, Henry S Heine, Robin B Gasser, Aria Eshraghi","doi":"10.1021/acsinfecdis.4c00547","DOIUrl":null,"url":null,"abstract":"<p><p>Tularemia is a deadly disease caused by <i>Francisella tularensis</i>, an emerging intracellular bacterial pathogen that can be disseminated rapidly through aerosols and vector-borne transmission. Recent surveillance data demonstrate an increasing incidence in several countries. Although clinical isolates of <i>Francisella</i> strains are sensitive to currently used antibiotics, engineered or horizontal acquisition of antibiotic resistance is a constant threat to public health. Therefore, the identification of antibiotics that target previously undrugged pathways is required to safeguard human health. An environmental pesticide that is registered for use in multiple countries, tolfenpyrad, shows promising activity to block <i>Francisella</i> growth; however, it is not a suitable antimicrobial candidate for use <i>in vivo</i> due to potential toxicity in humans and other animals. In this study, we applied a structure-activity relationship approach to tolfenpyrad to generate compounds with improved antibacterial activity and reduced toxicity. Through screening of a library of derivatives, we identified analogs with improved therapeutic windows compared with tolfenpyrad. Although structural diversity exists among these analogs, they inhibit the growth of <i>Francisella</i> species but not other Gram-negative or Gram-positive species. These compounds block intramacrophage growth of <i>F. novicida</i> and pathogenesis in an <i>in vivo</i> arthropod model of infection. Although the biochemical activity of these drugs is unknown, they appear to target the same pathway as the parent molecule because <i>F. novicida</i> mutants that are resistant to tolfenpyrad are also resistant to its analogs. Taken together, these findings suggest that these tolfenpyrad-derived compounds comprise a new class of <i>Francisella</i>-targeted antimicrobials and merit further evaluation and development.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tolfenpyrad Derivatives Exhibit Potent <i>Francisella</i>-Specific Antibacterial Activity without Toxicity to Mammalian Cells <i>In Vitro</i>.\",\"authors\":\"Nimra Khalid, Nicole Adams, Federico Cunha, Aya C Taki, Thuy G Le, Jonathan B Baell, Henry S Heine, Robin B Gasser, Aria Eshraghi\",\"doi\":\"10.1021/acsinfecdis.4c00547\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Tularemia is a deadly disease caused by <i>Francisella tularensis</i>, an emerging intracellular bacterial pathogen that can be disseminated rapidly through aerosols and vector-borne transmission. Recent surveillance data demonstrate an increasing incidence in several countries. Although clinical isolates of <i>Francisella</i> strains are sensitive to currently used antibiotics, engineered or horizontal acquisition of antibiotic resistance is a constant threat to public health. Therefore, the identification of antibiotics that target previously undrugged pathways is required to safeguard human health. An environmental pesticide that is registered for use in multiple countries, tolfenpyrad, shows promising activity to block <i>Francisella</i> growth; however, it is not a suitable antimicrobial candidate for use <i>in vivo</i> due to potential toxicity in humans and other animals. In this study, we applied a structure-activity relationship approach to tolfenpyrad to generate compounds with improved antibacterial activity and reduced toxicity. Through screening of a library of derivatives, we identified analogs with improved therapeutic windows compared with tolfenpyrad. Although structural diversity exists among these analogs, they inhibit the growth of <i>Francisella</i> species but not other Gram-negative or Gram-positive species. These compounds block intramacrophage growth of <i>F. novicida</i> and pathogenesis in an <i>in vivo</i> arthropod model of infection. Although the biochemical activity of these drugs is unknown, they appear to target the same pathway as the parent molecule because <i>F. novicida</i> mutants that are resistant to tolfenpyrad are also resistant to its analogs. Taken together, these findings suggest that these tolfenpyrad-derived compounds comprise a new class of <i>Francisella</i>-targeted antimicrobials and merit further evaluation and development.</p>\",\"PeriodicalId\":17,\"journal\":{\"name\":\"ACS Infectious Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-10-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsinfecdis.4c00547\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsinfecdis.4c00547","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Tolfenpyrad Derivatives Exhibit Potent Francisella-Specific Antibacterial Activity without Toxicity to Mammalian Cells In Vitro.
Tularemia is a deadly disease caused by Francisella tularensis, an emerging intracellular bacterial pathogen that can be disseminated rapidly through aerosols and vector-borne transmission. Recent surveillance data demonstrate an increasing incidence in several countries. Although clinical isolates of Francisella strains are sensitive to currently used antibiotics, engineered or horizontal acquisition of antibiotic resistance is a constant threat to public health. Therefore, the identification of antibiotics that target previously undrugged pathways is required to safeguard human health. An environmental pesticide that is registered for use in multiple countries, tolfenpyrad, shows promising activity to block Francisella growth; however, it is not a suitable antimicrobial candidate for use in vivo due to potential toxicity in humans and other animals. In this study, we applied a structure-activity relationship approach to tolfenpyrad to generate compounds with improved antibacterial activity and reduced toxicity. Through screening of a library of derivatives, we identified analogs with improved therapeutic windows compared with tolfenpyrad. Although structural diversity exists among these analogs, they inhibit the growth of Francisella species but not other Gram-negative or Gram-positive species. These compounds block intramacrophage growth of F. novicida and pathogenesis in an in vivo arthropod model of infection. Although the biochemical activity of these drugs is unknown, they appear to target the same pathway as the parent molecule because F. novicida mutants that are resistant to tolfenpyrad are also resistant to its analogs. Taken together, these findings suggest that these tolfenpyrad-derived compounds comprise a new class of Francisella-targeted antimicrobials and merit further evaluation and development.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.