ACS Infectious Diseases最新文献

{"title":"Time-Dependent Inhibition of Leucyl-tRNA-Synthetase (LeuRS): Insight into Target Vulnerability.","authors":"Mingqian Wang, YongLe He, Siobhan A Cohen, Amanda R Strohm, John D Haley, Stephen G Walker, M R K Alley, Peter J Tonge","doi":"10.1021/acsinfecdis.4c01017","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c01017","url":null,"abstract":"<p><p>The postantibiotic effect (PAE) is the persistent suppression of microbial growth following the removal of antimicrobial therapy. In general, antibiotics that generate a PAE are dosed less frequently, and thus, the PAE has important implications for dosing regimens. PAEs can arise through several mechanisms, including the extended occupancy of the drug target following drug elimination, and the correlation between drug-target residence time and PAE provides insight into target vulnerability. To assess the vulnerability of <i>Escherichia coli</i> leucyl-tRNA synthetase (ecLeuRS), which is an essential enzyme in protein synthesis, the time-dependent inhibition of the enzyme was studied by the benzoxaborole class of compounds that inhibit LeuRS by forming a stable LeuRS-tRNA^Leu-benzoxaborole adduct. Preincubation of epetraborole with ecLeuRS resulted in a decrease in the IC₅₀ value for enzyme inhibition from 38 to 3 nM, consistent with the slow formation of the final enzyme-inhibitor complex, and similar shifts in IC₅₀ were observed for three other benzoxaboroles. The benzoxaboroles generated short PAEs (<1 h) in <i>E. coli</i>, however, the PAE values of AN3334 and epetraborole increased from 0.88 to 1.70-3 h when a sub-MIC concentration of the aminoglycoside tobramycin was included in the media. pSILAC revealed that the synthesis rate of ecLeuRS was reduced 1.6-fold in the presence of sub-MIC tobramycin, reinforcing the role that protein turnover plays in target vulnerability.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of a New Purine Analogue Class with Antifungal Activity and Improved Potency against Fungal IP_3-4K.","authors":"Desmarini Desmarini, Daniel Truong, Pooja Sethiya, Guizhen Liu, Bethany Bowring, Henning Jessen, Hue Dinh, Amy K Cain, Philip E Thompson, Julianne T Djordjevic","doi":"10.1021/acsinfecdis.4c00975","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00975","url":null,"abstract":"<p><p>New antifungals are urgently needed to treat deadly fungal infections. Targeting the fungal inositol polyphosphate kinases IP_3-4K (Arg1) and IP₆K (Kcs1) is a promising strategy as it has been validated genetically to be crucial for fungal virulence but never pharmacologically. We now report the synthesis of <b>DT-23</b>, an analogue of <i>N</i>2-(<i>m</i>-trifluorobenzylamino)-<i>N</i>6-(<i>p</i>-nitrobenzylamino)purine (<b>TNP</b>), and demonstrate that it more potently inhibits recombinant Arg1 from the priority pathogen <i>Cryptococcus neoformans</i> (<i>Cn</i>) (IC₅₀ = 0.6 μM) than previous analogues (IC₅₀ = 10-30 μM). <b>DT-23</b> also inhibits recombinant Kcs1 with similar potency (IC₅₀ = 0.68 μM) and Arg1 and Kcs1 activity <i>in vivo</i>. Unlike previous analogues, <b>DT-23</b> inhibits fungal growth (MIC₅₀ = 15 μg/mL) and only 1.5 μg/mL synergizes with Amphotericin B to kill <i>Cn in vitro</i>. <b>DT-23</b>/Amphotericin B is also more protective against <i>Cn</i> infection in an insect model compared to each drug alone. Transcription profiling shows that <b>DT-23</b> impacts early stages in IP synthesis and cellular functions impacted by IPK gene deletion, consistent with its targeted effect. This study establishes the first pharmacological link between inhibiting IPK activity and antifungal activity, providing tools for studying IPK function and a foundation to potentially develop a new class of antifungal drug.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Class of Iron-Grabbing Compounds with Antiplasmodial Activity: Impact of Coordination Structures and Electronic Regularity on the Intraerythrocytic Growth Cycle of Plasmodium falciparum","authors":"Akira Wada*,&nbsp; and ,&nbsp;Hiroko Asahi,&nbsp;","doi":"10.1021/acsinfecdis.4c0084610.1021/acsinfecdis.4c00846","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00846https://doi.org/10.1021/acsinfecdis.4c00846","url":null,"abstract":"<p >Innovative antimalarials are required to combat malaria, a global infectious disease caused by <i>Plasmodium falciparum</i>. To explore the untapped antiplasmodial compounds that can target the iron source vital at the blood stages of <i>P. falciparum</i>, we investigated the antiplasmodial activities of natural siderophores and synthetic compounds with metal-binding affinity. The assessment of their IC₅₀ values and spectroscopic analytical data revealed that terpyridyl compounds specifically bound to target Fe(II) ions and strongly induced the growth inhibition of intraerythrocytic parasites. Furthermore, the IC₅₀ values of the 4,4′,4′′-substituted terpyridines were linearly correlated with the sum of the <i>para</i> Hammett constants of their substitutions, suggesting that their growth inhibitory effects depended on the electronic states of the coordinating nitrogen atoms. Considering the specific developmental blockage at the trophozoite stage and selective antiplasmodial activities of the iron-grabbing compounds, these findings provide insights into the development of antimalarials that can disrupt iron homeostasis.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"799–804 799–804"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of a New Purine Analogue Class with Antifungal Activity and Improved Potency against Fungal IP3–4K","authors":"Desmarini Desmarini,&nbsp;Daniel Truong,&nbsp;Pooja Sethiya,&nbsp;Guizhen Liu,&nbsp;Bethany Bowring,&nbsp;Henning Jessen,&nbsp;Hue Dinh,&nbsp;Amy K. Cain,&nbsp;Philip E. Thompson* and Julianne T. Djordjevic*,&nbsp;","doi":"10.1021/acsinfecdis.4c0097510.1021/acsinfecdis.4c00975","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00975https://doi.org/10.1021/acsinfecdis.4c00975","url":null,"abstract":"<p >New antifungals are urgently needed to treat deadly fungal infections. Targeting the fungal inositol polyphosphate kinases IP_3–4K (Arg1) and IP₆K (Kcs1) is a promising strategy as it has been validated genetically to be crucial for fungal virulence but never pharmacologically. We now report the synthesis of <b>DT-23</b>, an analogue of <i>N</i>2-(<i>m</i>-trifluorobenzylamino)-<i>N</i>6-(<i>p</i>-nitrobenzylamino)purine (<b>TNP</b>), and demonstrate that it more potently inhibits recombinant Arg1 from the priority pathogen <i>Cryptococcus neoformans</i> (<i>Cn</i>) (IC₅₀ = 0.6 μM) than previous analogues (IC₅₀ = 10–30 μM). <b>DT-23</b> also inhibits recombinant Kcs1 with similar potency (IC₅₀ = 0.68 μM) and Arg1 and Kcs1 activity <i>in vivo</i>. Unlike previous analogues, <b>DT-23</b> inhibits fungal growth (MIC₅₀ = 15 μg/mL) and only 1.5 μg/mL synergizes with Amphotericin B to kill <i>Cn in vitro</i>. <b>DT-23</b>/Amphotericin B is also more protective against <i>Cn</i> infection in an insect model compared to each drug alone. Transcription profiling shows that <b>DT-23</b> impacts early stages in IP synthesis and cellular functions impacted by IPK gene deletion, consistent with its targeted effect. This study establishes the first pharmacological link between inhibiting IPK activity and antifungal activity, providing tools for studying IPK function and a foundation to potentially develop a new class of antifungal drug.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"940–953 940–953"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00975","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Class of Iron-Grabbing Compounds with Antiplasmodial Activity: Impact of Coordination Structures and Electronic Regularity on the Intraerythrocytic Growth Cycle of <i>Plasmodium falciparum</i>.","authors":"Akira Wada, Hiroko Asahi","doi":"10.1021/acsinfecdis.4c00846","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00846","url":null,"abstract":"<p><p>Innovative antimalarials are required to combat malaria, a global infectious disease caused by <i>Plasmodium falciparum</i>. To explore the untapped antiplasmodial compounds that can target the iron source vital at the blood stages of <i>P. falciparum</i>, we investigated the antiplasmodial activities of natural siderophores and synthetic compounds with metal-binding affinity. The assessment of their IC₅₀ values and spectroscopic analytical data revealed that terpyridyl compounds specifically bound to target Fe(II) ions and strongly induced the growth inhibition of intraerythrocytic parasites. Furthermore, the IC₅₀ values of the 4,4',4''-substituted terpyridines were linearly correlated with the sum of the <i>para</i> Hammett constants of their substitutions, suggesting that their growth inhibitory effects depended on the electronic states of the coordinating nitrogen atoms. Considering the specific developmental blockage at the trophozoite stage and selective antiplasmodial activities of the iron-grabbing compounds, these findings provide insights into the development of antimalarials that can disrupt iron homeostasis.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutical Potential and Immunomodulatory Profile of <i>Arthrospira platensis</i> Compounds against Chagas Disease.","authors":"Maria Rafaele Oliveira Bezerra da Silva, Ana Carla da Silva, Byannca de Carvalho Torreão, Romero Marcos Pedrosa Brandão Costa, Raquel Pedrosa Bezerra, Silvana de Fátima Ferreira da Silva, Maria Luiza Vilela Oliva, Lícya Samara da Silva Xavier, Isabelle F T Viana, Roberto Dias Lins, Virginia Maria Barros de Lorena, Daniela de Araújo Viana Marques","doi":"10.1021/acsinfecdis.4c01052","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c01052","url":null,"abstract":"<p><p><i>Arthrospira platensis</i>, an ancient cyanobacterium, is rich in bioactive compounds with therapeutic potential, supporting its use in studies for various health conditions, including infectious and chronic diseases. This study aimed to evaluate the antiparasitic, cytotoxic, and immunomodulatory activities of <i>A. platensis</i> compounds against <i>Trypanosoma cruzi</i>. Peripheral Blood Mononuclear Cells (PBMC) and <i>T. cruzi</i> trypomastigotes were cultured for cytotoxic and antiparasitic analyses. Cytotoxicity was assessed in PBMC treated with different concentrations of crude extract, obtained by mechanical agitation in 0.1 M TRIS-HCl buffer (pH 7.2), and purified protein by DEAE-Sephadex A-50 chromatography and FPLC. Immune response was analyzed in infected and uninfected PBMC by measuring cytokines (IFN-γ, TNF, IL-2, IL-6, and IL-10) after treatment with purified protein and benznidazole. <i>In vitro</i> experiments showed that both crude extract and a 15 kDa purified protein were toxic to trypomastigotes in a dose-dependent manner, eliminating over 80% of the parasite at 1000 and 200 μg/mL, respectively. Both the extract and protein were nontoxic to PBMC, with the protein (SI: 20.7) being more selective than benznidazole (SI: 11.5). Results indicated that the purified protein modulated the immune response in <i>T. cruzi</i>-infected individuals, inducing a protective Th1 response while controlling an excessive inflammatory response with appropriate IL-10 levels. The anti-<i>T. cruzi</i> activity of this protein, alone or in combination with the commercial drug, suggests it could be a low-cost, safer, and more tolerable therapy for Chagas disease treatment.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutical Potential and Immunomodulatory Profile of Arthrospira platensis Compounds against Chagas Disease","authors":"Maria Rafaele Oliveira Bezerra da Silva,&nbsp;Ana Carla da Silva,&nbsp;Byannca de Carvalho Torreão,&nbsp;Romero Marcos Pedrosa Brandão Costa,&nbsp;Raquel Pedrosa Bezerra,&nbsp;Silvana de Fátima Ferreira da Silva,&nbsp;Maria Luiza Vilela Oliva,&nbsp;Lícya Samara da Silva Xavier,&nbsp;Isabelle F.T. Viana,&nbsp;Roberto Dias Lins,&nbsp;Virginia Maria Barros de Lorena and Daniela de Araújo Viana Marques*,&nbsp;","doi":"10.1021/acsinfecdis.4c0105210.1021/acsinfecdis.4c01052","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c01052https://doi.org/10.1021/acsinfecdis.4c01052","url":null,"abstract":"<p ><i>Arthrospira platensis</i>, an ancient cyanobacterium, is rich in bioactive compounds with therapeutic potential, supporting its use in studies for various health conditions, including infectious and chronic diseases. This study aimed to evaluate the antiparasitic, cytotoxic, and immunomodulatory activities of <i>A. platensis</i> compounds against <i>Trypanosoma cruzi</i>. Peripheral Blood Mononuclear Cells (PBMC) and <i>T. cruzi</i> trypomastigotes were cultured for cytotoxic and antiparasitic analyses. Cytotoxicity was assessed in PBMC treated with different concentrations of crude extract, obtained by mechanical agitation in 0.1 M TRIS-HCl buffer (pH 7.2), and purified protein by DEAE-Sephadex A-50 chromatography and FPLC. Immune response was analyzed in infected and uninfected PBMC by measuring cytokines (IFN-γ, TNF, IL-2, IL-6, and IL-10) after treatment with purified protein and benznidazole. <i>In vitro</i> experiments showed that both crude extract and a 15 kDa purified protein were toxic to trypomastigotes in a dose-dependent manner, eliminating over 80% of the parasite at 1000 and 200 μg/mL, respectively. Both the extract and protein were nontoxic to PBMC, with the protein (SI: 20.7) being more selective than benznidazole (SI: 11.5). Results indicated that the purified protein modulated the immune response in <i>T. cruzi</i>-infected individuals, inducing a protective Th1 response while controlling an excessive inflammatory response with appropriate IL-10 levels. The anti-<i>T. cruzi</i> activity of this protein, alone or in combination with the commercial drug, suggests it could be a low-cost, safer, and more tolerable therapy for Chagas disease treatment.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"1008–1017 1008–1017"},"PeriodicalIF":4.0,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c01052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host–Pathogen Cellular Communication: The Role of Dynamin, Clathrin, and Macropinocytosis in the Uptake of Giardia-Derived Extracellular Vesicles","authors":"Bruna Sabatke,&nbsp;Izadora V Rossi,&nbsp;Leticia Bonato,&nbsp;Sarah Fucio,&nbsp;Alba Cortés,&nbsp;Antonio Marcilla and Marcel I. Ramirez*,&nbsp;","doi":"10.1021/acsinfecdis.4c0099610.1021/acsinfecdis.4c00996","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00996https://doi.org/10.1021/acsinfecdis.4c00996","url":null,"abstract":"<p ><i>Giardia intestinalis</i>, a protozoan causing giardiasis, disrupts gastrointestinal health through complex host–parasite interactions. This study explores the differential uptake mechanisms of extracellular vesicles (EVs) derived from <i>Giardia</i> (gEVs), host cells (hEVs), and the host–parasite interaction (intEVs) in intestinal Caco-2 cells. Results show that intEVs are internalized more rapidly than gEVs and hEVs, underscoring their pivotal role in pathogenesis. To delineate uptake pathways, various endocytosis inhibitors were applied, and clathrin-mediated endocytosis inhibition using monodansylcadaverine (MDC) significantly reduced intEV and gEV uptake, confirming the role of clathrin-mediated endocytosis (CME). The use of dynasore, a dynamin inhibitor, strongly reduced the internalization of all EV types, demonstrating that uptake is dynamin-dependent. In contrast, methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts and caveolae-mediated pathways, had no effect on EV uptake, indicating that caveolae are not involved in this process. Furthermore, inhibition of Na⁺/H⁺ exchange and phosphoinositide 3-kinase activity, both essential for macropinocytosis, also led to a significant reduction in intEV internalization. These findings strongly support that gEVs are internalized primarily through a dynamin- and clathrin-dependent pathway, independent of caveolae and lipid rafts, but modulated by tyrosine kinase signaling and macropinocytosis. These insights into selective and comprehensive inhibition pathways offer promising therapeutic targets to mitigate giardiasis.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"954–962 954–962"},"PeriodicalIF":4.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00996","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host-Pathogen Cellular Communication: The Role of Dynamin, Clathrin, and Macropinocytosis in the Uptake of Giardia-Derived Extracellular Vesicles.","authors":"Bruna Sabatke, Izadora V Rossi, Leticia Bonato, Sarah Fucio, Alba Cortés, Antonio Marcilla, Marcel I Ramirez","doi":"10.1021/acsinfecdis.4c00996","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00996","url":null,"abstract":"<p><p><i>Giardia intestinalis</i>, a protozoan causing giardiasis, disrupts gastrointestinal health through complex host-parasite interactions. This study explores the differential uptake mechanisms of extracellular vesicles (EVs) derived from <i>Giardia</i> (gEVs), host cells (hEVs), and the host-parasite interaction (intEVs) in intestinal Caco-2 cells. Results show that intEVs are internalized more rapidly than gEVs and hEVs, underscoring their pivotal role in pathogenesis. To delineate uptake pathways, various endocytosis inhibitors were applied, and clathrin-mediated endocytosis inhibition using monodansylcadaverine (MDC) significantly reduced intEV and gEV uptake, confirming the role of clathrin-mediated endocytosis (CME). The use of dynasore, a dynamin inhibitor, strongly reduced the internalization of all EV types, demonstrating that uptake is dynamin-dependent. In contrast, methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts and caveolae-mediated pathways, had no effect on EV uptake, indicating that caveolae are not involved in this process. Furthermore, inhibition of Na⁺/H⁺ exchange and phosphoinositide 3-kinase activity, both essential for macropinocytosis, also led to a significant reduction in intEV internalization. These findings strongly support that gEVs are internalized primarily through a dynamin- and clathrin-dependent pathway, independent of caveolae and lipid rafts, but modulated by tyrosine kinase signaling and macropinocytosis. These insights into selective and comprehensive inhibition pathways offer promising therapeutic targets to mitigate giardiasis.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and Cheminformatic Characterization of Mycobacterium tuberculosis Inhibitors Discovered in the Molecular Libraries Small Molecule Repository","authors":"Ifeanyichukwu E. Eke,&nbsp;John T. Williams and Robert B. Abramovitch*,&nbsp;","doi":"10.1021/acsinfecdis.4c0093610.1021/acsinfecdis.4c00936","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00936https://doi.org/10.1021/acsinfecdis.4c00936","url":null,"abstract":"<p >High-throughput screening (HTS) of small molecules is a starting point for many drug development pipelines, including tuberculosis. These screens often result in multiple hits whose mechanisms of action remain unknown. From our initial HTS of the Molecular Libraries Small Molecule Repository (MLSMR), we cherry-picked 935 compounds that inhibited the growth of <i>Mycobacterium tuberculosis</i> and set out to provide an early assessment of their antimycobacterial properties and mechanism of action. To characterize the MLSMR Mtb growth inhibitors, a combination of cheminformatics and targeted mutant screening against mutants in <i>katG</i>, <i>hadAB</i>, and a mixed pool of <i>mmpL3</i> mutants was used to characterize the hits. As a validation of this approach, we identified 101 isoniazid analogs that predictably lose all their antimycobacterial activities against the <i>katG</i> mutant. Interestingly, eight isoniazid analogs retain part of their activity against the mutant, suggesting an alternative KatG-independent mechanism. This approach also identified new compounds belonging to already known scaffolds that target HadAB or MmpL3. Additionally, we explored the nitro-containing compounds in our data set and discovered nitrofuranyl benzothiazoles that show enhanced activity against the <i>mmpL3</i> and <i>katG</i> mutants, a phenomenon known as collateral sensitivity. Overall, this study will serve as an important resource for further follow-up studies of antitubercular small molecules in the MLSMR library and provide a well-characterized training set for artificial intelligence-driven antimycobacterial drug discovery.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"882–893 882–893"},"PeriodicalIF":4.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00936","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}