ACS Infectious Diseases最新文献

{"title":"In Vitro and In Vivo Studies on a Mononuclear Ruthenium Complex Reveals It is a Highly Effective, Fast-Acting, Broad-Spectrum Antimicrobial in Physiologically Relevant Conditions.","authors":"Adam M Varney, Kirsty L Smitten, Hannah M Southam, Simon D Fairbanks, Craig C Robertson, Jim A Thomas, Samantha McLean","doi":"10.1021/acsinfecdis.4c00447","DOIUrl":"10.1021/acsinfecdis.4c00447","url":null,"abstract":"<p><p>The crystal structure of a previously reported antimicrobial Ru^II complex that targets bacterial DNA is presented. Studies utilizing clinical isolates of Gram-negative bacteria that cause catheter-associated urinary tract infection, (CA)UTI, in media that model urine and plasma reveal that good antimicrobial activity is maintained in all conditions tested. Experiments with a series of <i>Staphylococcus aureus</i> clinical isolates show that, unlike the majority of previously reported Ru^II-based antimicrobial leads, the compound retains its potent activity even in MRSA strains. Furthermore, experiments using bacteria in early exponential growth and at different pHs reveal that the compound also retains its activity across a range of conditions that are relevant to those encountered in clinical settings. Combinatorial studies involving cotreatment with conventional antibiotics or a previously reported analogous dinuclear Ru^II complex showed no antagonistic effects. In fact, although all combinations show distinct additive antibacterial activity, in one case, this effect approaches synergy. It was found that the <i>Galleria Mellonella</i> model organism infected with a multidrug resistant strain of the ESKAPE pathogen <i>Acinetobacter baumannii</i> could be successfully treated and totally cleared within 48 h after a single dose of the lead complex with no detectable deleterious effect to the host.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3346-3357"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895976","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":"Cocktail Approach with Polyserotonin Nanoparticles and Peptides for Treatment of <i>Streptococcus mutans</i>.","authors":"Keuna Jeon, Nesha May O Andoy, Delphine Dufour, Jessica Y C Yang, Céline M Lévesque, Ruby May A Sullan","doi":"10.1021/acsinfecdis.4c00107","DOIUrl":"10.1021/acsinfecdis.4c00107","url":null,"abstract":"<p><p>Dental plaque, formed by a <i>Streptococcus mutans</i> biofilm, is a major contributor to cavity formation. While antimicrobial strategies exist, the growing risk of antibiotic resistance necessitates alternative therapeutic solutions. Polyserotonin nanoparticles (PSeNPs), recently recognized for their photothermal property and promising biomedical applications, open up a new avenue for antimicrobial use. Here, we introduced a UV-initiated synthetic route for PSeNPs with improved yield. Using these PSeNPs, a cocktail treatment to reduce the viability of this cavity-causing bacteria was developed. This cocktail comprises an <i>S. mutans</i>-targeting antimicrobial peptide (GH12), an intraspecies competence-stimulating peptide that triggers altruistic cell death in <i>S. mutans</i>, and laser-activated heating of PSeNPs. The \"peptide + PSeNP + laser\" combination effectively inhibits <i>S. mutans</i> growth in both planktonic and biofilm states. Moreover, the cocktail approach remains effective in reducing the viability of <i>S. mutans</i> in a more virulent dual-species biofilm with <i>Candida albicans</i>. Overall, our results reinforce the utility of a multipronged therapeutic strategy to reduce cariogenic bacteria in the complex model oral biofilm.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3176-3184"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998823","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":"Identifying Rab2 Protein as a Key Interactor of Centrin1 Essential for <i>Leishmania donovani</i> Growth.","authors":"Roshanara, Rati Tandon, Mirza Sarwar Baig, Sanchita Das, Rahul Srivastava, Niti Puri, Hira L Nakhasi, Angamuthu Selvapandiyan","doi":"10.1021/acsinfecdis.4c00351","DOIUrl":"10.1021/acsinfecdis.4c00351","url":null,"abstract":"<p><p>Previously, we have demonstrated that deletion of a growth-regulating gene (<i>LdCen1</i>) in the <i>Leishmania donovani</i> parasite (<i>LdCen1</i>^<i>-/-</i>) attenuated the parasite's intracellular amastigote growth but not the growth of extracellular promastigotes. <i>LdCen1</i>^<i>-/-</i> parasites were found to be safe and efficacious against homologous and heterologous <i>Leishmania</i> species as a vaccine candidate in animal models. The reason for the differential growth of <i>LdCen1</i>^<i>-/-</i> between the two stages of the parasite needed investigation. Here, we report that <i>LdCen1</i> interacts with a novel Ras-associated binding protein in <i>L. donovani</i> (LdRab2) to compensate for the growth of <i>LdCen1</i>^<i>-/-</i> promastigotes. LdRab2 was isolated by protein pull-down from the parasite lysate, followed by nano-LC-MS/MS identification. The RAB domain sequence and the functional binding partners of the LdRab2 protein were predicted via Search Tool for the Retrieval of Interacting Proteins (STRING) analysis. The closeness of the LdRab2 protein to other reported centrin-binding proteins with different functions in other organisms was analyzed via phylogenetic analysis. Furthermore, <i>in vitro</i> and <i>in silico</i> analyses revealed that LdRab2 also interacts with other <i>L. donovani</i> centrins 3-5. Since centrin is a calcium-binding protein, we further investigated calcium-based interactions and found that the binding of LdRab2 to LdCen1 and LdCen4 is calcium-independent, whereas the interactions with LdCen3 and LdCen5 are calcium-dependent. The colocalization of LdCen1 and LdRab2 at the cellular basal-body region by immunofluorescence supports their possible functional association. The elevated expression of the LdRab2 protein in the mutant promastigotes suggested a probable role in compensating for the promastigote growth of this mutant strain, probably in association with other parasite centrins.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3273-3288"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895975","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 and Biological Evaluation of Cyanoacrylamides and 5-Iminopyrrol-2-Ones Against <i>Naegleria fowleri</i>.","authors":"Javier Chao-Pellicer, Samuel Delgado-Hernández, Iñigo Arberas-Jiménez, Ines Sifaoui, David Tejedor, Fernando García-Tellado, José E Piñero, Jacob Lorenzo-Morales","doi":"10.1021/acsinfecdis.4c00439","DOIUrl":"10.1021/acsinfecdis.4c00439","url":null,"abstract":"<p><p>Primary amoebic meningoencephalitis is caused by the free-living amoeba <i>Naegleria fowleri</i>. The lack of standardized treatment has significantly contributed to the high fatality rates observed in reported cases. Therefore, this study aims to explore the anti-<i>Naegleria</i> activity of eight synthesized cyanoacrylamides and 5-iminopyrrol-2-ones. Notably, QOET-109, QOET-111, QOET-112, and QOET-114 exhibited a higher selectivity index against <i>Naegleria</i> compared to those of the rest of the compounds. Subsequently, these chemicals were assessed against the resistant stage of <i>N. fowleri</i>, demonstrating activity similar to that observed in the vegetative stage. Moreover, characteristic events of programmed cell death were evidenced, including chromatin condensation, increased plasma membrane permeability, mitochondrial damage, and heightened oxidative stress, among others. Finally, this research demonstrated the <i>in vitro</i> activity of the cyanoacrylamide and 5-iminopyrrol-2-one molecules, as well as the induction of metabolic event characteristics of regulated cell death in <i>Naegleria fowleri</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3332-3345"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904953","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":"Biochemical Characterization of Recombinant <i>Enterococcus faecalis</i> EntV Peptide to Elucidate Its Antihyphal and Antifungal Mechanisms against <i>Candida albicans</i>.","authors":"Jia Li Fong, Victor Ong Eng Yong, Claresta Yeo, Christopher Adamson, Lanxin Li, Dan Zhang, Yuan Qiao","doi":"10.1021/acsinfecdis.4c00515","DOIUrl":"10.1021/acsinfecdis.4c00515","url":null,"abstract":"<p><p><i>Candida albicans</i> is a common opportunistic fungus in humans, whose morphological switch between yeast and hyphae forms represents a key virulence trait. Developing strategies to inhibit <i>C. albicans</i> hyphal growth may provide insights into designs of novel antivirulent therapeutics. Importantly, the gut commensal bacterium, <i>Enterococcus faecalis</i>, secretes a bacteriocin EntV which has potent antivirulent and antifungal effects against <i>C. albicans</i> in infection models; however, hampered by the challenges to access large quantities of bioactive EntV, the detailed understanding of its mechanisms on <i>C. albicans</i> has remained elusive. In this work, we biochemically reconstituted the proteolytic cleavage reaction to obtain recombinant EntV⁸⁸-His₆ on a large preparative scale, providing facile access to the C-terminal EntV construct. Under <i>in vitro</i> <i>C. albicans</i> hyphal assay with specific inducers, we demonstrated that EntV⁸⁸-His₆ exhibits potent bioactivity against GlcNAc-triggered hyphal growth. Moreover, with fluorescent FITC-EntV⁸⁸-His₆, we revealed that EntV⁸⁸-His₆ enters <i>C. albicans</i> via endocytosis and perturbs the proper localization of the polarisome scaffolding Spa2 protein. Our findings provide important clues on EntV's mechanism of action. Surprisingly, we showed that EntV⁸⁸-His₆ does not affect <i>C. albicans</i> yeast cell growth but potently exerts cytotoxicity against <i>C. albicans</i> under hyphal-inducing conditions <i>in vitro</i>. The combination of EntV⁸⁸-His₆ and GlcNAc displays rapid killing of <i>C. albicans</i>, rendering it a promising antivirulent and antifungal agent.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3408-3418"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974360","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":"High Therapeutic Index α-Helical AMPs and Their Therapeutic Potential on Bacterial Lung and Skin Wound Infections.","authors":"Xu Ouyang, Beibei Li, Tingting Yang, Yinyin Yang, Zufang Ba, Jingying Zhang, Ping Yang, Yao Liu, Yu Wang, Yuhuan Zhao, Wenbo Mao, Xiaoyan Wu, Xiaoxuan Zeng, Chao Zhong, Hui Liu, Yun Zhang, Sanhu Gou, Jingman Ni","doi":"10.1021/acsinfecdis.3c00706","DOIUrl":"10.1021/acsinfecdis.3c00706","url":null,"abstract":"<p><p>Antimicrobial peptides (AMPs) possess strong antibacterial activity and low drug resistance, making them ideal candidates for bactericidal drugs for addressing the issue of traditional antibiotic resistance. In this study, a template (G(XXKK)<i>_n</i>I, G = Gly; X = Leu, Ile, Phe, or Trp; <i>n</i> = 2, 3, or 4; K = Lys; I = Ile.) was employed for the devised of a variety of novel α-helical AMPs with a high therapeutic index. The AMP with the highest therapeutic index, WK₂, was ultimately chosen following a thorough screening process. It demonstrates broad-spectrum and potent activity against both standard and multidrug-resistant bacteria, while also showing low hemolysis and rapid and efficient time-kill kinetics. Additionally, WK₂ exhibits excellent efficacy in treating mouse models of <i>Klebsiella pneumonia</i>-induced lung infections and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-induced skin wound infections while demonstrating good safety profiles <i>in vivo</i>. In conclusion, the template-based design methodology for novel AMPs with high therapeutic indices offers new insights into addressing antibiotic resistance problems. WK₂ represents a promising antimicrobial agent.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3138-3157"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974361","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":"ASLdC3: A Derivative of Acidic Sophorolipid Disrupts Mitochondrial Function, Induces ROS Generation, and Inhibits Biofilm Formation in <i>Candida albicans</i>.","authors":"Sandal Deep Basotra, Yachna Kumari, Mansi Vij, Arpit Tyagi, Deepak Sharma, Mani Shankar Bhattacharyya","doi":"10.1021/acsinfecdis.4c00155","DOIUrl":"10.1021/acsinfecdis.4c00155","url":null,"abstract":"<p><p>Fungal infections account for more than 140 million cases of severe and life-threatening conditions each year, causing approximately 1.7 million deaths annually. <i>Candida albicans</i> and related species are the most common human fungal pathogens, causing both superficial (mucosal and cutaneous) and life-threatening invasive infections (candidemia) with a 40-75% mortality rate. Among many virulence factors of <i>Candida albicans</i>, morphological transition from yeast to hyphae, secretion of hydrolytic enzymes, and formation of biofilms are considered to be crucial for pathogenicity. However, the arsenals for the treatment against these pathogens are restricted to only a few classes of approved drugs, the efficacy of which is being compromised by host toxicity, fungistatic activity, and the emergence of drug resistance. In this study, we have described the development of a molecule, exhibiting excellent antifungal activity (MIC 8 μg/mL), by tailoring acidic sophorolipids with aryl alcohols via enzyme catalysis. This novel derivative, ASLdC3, is a surface-active compound that lowers the surface tension of the air-water interface up to 2-fold before reaching the critical micelle concentration of 25 μg/mL. ASLdC3 exhibits excellent antibiofilm properties against <i>Candida albicans</i> and other nonalbicans <i>Candida</i> species. The molecule primarily exhibits its antifungal activity by perturbing mitochondrial function through the alteration of the mitochondrial membrane potential (MMP) and generation of reactive oxygen species (ROS). The ROS damages fungal cell membrane function and cell wall integrity, eventually leading to cell death. ASLdC3 was found to be nontoxic in in vitro assay and nonhemolytic. Besides, it does not cause toxicity in the <i>C. elegans</i> model. Our study provides a valuable foundation for the potential of acidic sophorolipid as a nontoxic, biodegradable precursor for the design and synthesis of novel molecules for use as antimicrobial drugs as well as for other clinical applications.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3185-3201"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873677","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":"STING Agonist Induced Innate Immune Responses Drive Anti-Respiratory Virus Activity <i>In Vitro</i> with Limited Antiviral Efficacy <i>In Vivo</i>.","authors":"Rebecca Broeckel, Amanda Browne, Scott Sucoloski, Juan Cantizani, Juliet K Simpson, Scott Pesiridis, Joshi M Ramanjulu, Neil Stokes, Priya Luthra","doi":"10.1021/acsinfecdis.4c00504","DOIUrl":"10.1021/acsinfecdis.4c00504","url":null,"abstract":"<p><p>The emergence of SARS-CoV-2 and seasonal outbreaks of other respiratory viruses highlight the urgent need for broad-spectrum antivirals to treat respiratory tract infections. Stimulator of interferon genes (STING) is a key component of innate immune signaling and plays a critical role in protection of the host against viral infections. Previously the STING agonist diABZI-4, a diamidobenzimidazole-based compound, demonstrated protection against SARS-CoV-2 both <i>in vitro</i> and <i>in vivo</i>. However, its broad-spectrum antiviral activity against other respiratory viruses in human airway epithelial cells, which are the primary targets of these infections, is not well established. In this study, we demonstrated that diABZI-4 stimulated robust innate immune responses protecting lung cells against a wide range of respiratory viruses, including influenza A virus (IAV), common cold coronaviruses, SARS-CoV-2, human rhinovirus (HRV), and human parainfluenza virus. diABZI-4 was highly active in physiologically relevant human airway epithelial tissues grown at the air-liquid interface, blocking replication of IAV, SARS-CoV-2, and HRV in these tissues. Furthermore, treatment of macrophages with diABZI-4 resulted in the secretion of cytokines that protected the primary airway epithelial cells from IAV infection. Despite the promising <i>in vitro</i> pan-antiviral activity, intranasal administration of diABZI-4 in mice provided early, but not sustained, inhibition of IAV replication in the lungs. These data highlight the complexities of the relationship between timing of STING agonist-driven inflammatory responses and viral replication dynamics, emphasizing the development challenge posed by STING agonists as potential therapeutics against respiratory viruses.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3392-3407"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102101","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":"ErpY-like Protein Interaction with Host Thrombin and Fibrinogen Intervenes the Plasma Coagulation through Extrinsic and Intrinsic Pathways.","authors":"Saswat Hota, Manish Kumar","doi":"10.1021/acsinfecdis.4c00266","DOIUrl":"10.1021/acsinfecdis.4c00266","url":null,"abstract":"<p><p>The survival and proliferation of pathogenic <i>Leptospira</i> within a host are complex phenomena that require careful consideration. The ErpY-like lipoprotein, found on the outer membrane surface of <i>Leptospira</i>, plays a crucial role in enhancing the bacterium's pathogenicity. The rErpY-like protein, in its recombinant form, contributes significantly to spirochete virulence by interacting with various host factors, including host complement regulators. This interaction facilitates the bacterium's evasion of the host complement system, thereby augmenting its overall pathogenicity. The rErpY-like protein exhibits a robust binding affinity to soluble fibrinogen, a vital component of the host coagulation system. In this study, we demonstrate that the rErpY-like protein intervenes in the clotting process of the platelet-poor citrated plasma of bovines and humans in a concentration-dependent manner. It significantly reduces clot density, alters the viscoelastic properties of the clot, and diminishes the average clotting rate in plasma. Furthermore, the ErpY-like protein inhibits thrombin-catalyzed fibrin formation in a dose-dependent manner and exhibits saturable binding to thrombin, suggesting its significant role in leptospiral infection. These findings provide compelling evidence for the anticoagulant effect of the ErpY-like lipoprotein and its significant role in leptospiral infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3256-3272"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131136","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 Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase","authors":"Cara Adolph, Kiel Hards, Zoe C. Williams, Chen-Yi Cheung, Laura M. Keighley, William J. Jowsey, Matson Kyte, Daniel Ken Inaoka, Kiyoshi Kita, Jared S. Mackenzie, Adrie J.C. Steyn, Zhengqiu Li, Ming Yan, Guo-Bao Tian, Tianyu Zhang, Xiaobo Ding, Daniel P. Furkert, Margaret A. Brimble, Anthony J.R. Hickey, Matthew B. McNeil, Gregory M. Cook","doi":"10.1021/acsinfecdis.3c00655","DOIUrl":"https://doi.org/10.1021/acsinfecdis.3c00655","url":null,"abstract":"Drug-resistant <i>Mycobacterium tuberculosis</i> is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in <i>M. tuberculosis</i> under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in <i>M. tuberculosis</i>, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of <i>M. tuberculosis</i>. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against <i>M. tuberculosis</i>.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"6 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219423","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}