ACS Infectious Diseases最新文献

{"title":"Mycobacterium tuberculosis Rv3248c Inhibits Type I Interferon Response and Promotes Intracellular Survival by Mediating Ubiquitin-Proteasome-Dependent Degradation of TBK1","authors":"Zhengzhong Xu,&nbsp;Min Geng,&nbsp;Zhifang Zhang,&nbsp;Wanying Wu,&nbsp;Jiaxu Wan,&nbsp;Tian Tian,&nbsp;Chengkun Zheng,&nbsp;Xiang Chen,&nbsp;Xin-an Jiao","doi":"10.1021/acsinfecdis.6c00364","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00364","url":null,"abstract":"<p><em>Mycobacterium tuberculosis</em> (<em>M. tb</em>) is a leading cause of infectious diseasemortalityworldwide, and <em>M. tb</em> subverts host immunity to persistintracellularly. Type I interferon (IFN-I) modulates host defenseduring <em>M. tb</em> infection, but the mechanisms controllingtheir induction remain incompletely defined. In this research, a previouslyuncharacterized mycobacterial factor, <em>M. tb</em> Rv3248c,which regulates IFN-I response, was identified using pull-down andmass spectrometry. Overexpression of Rv3248c suppresses IFN-βexpression in macrophages at both the transcriptional and proteinlevels. In addition, it also enhances intracellular bacterial load,whereas in bone marrow-derived macrophages (BMDMs) from Ifnar1^–/– C57BL/6 mice, the difference of bacterialload was no longer statistically significant, suggesting that Rv3248cenhances mycobacterial survival in IFN-I-dependent manner. Furthermore,the study shows that <em>M. tb</em> Rv3248c inhibits IFN-Iresponse via the cGAS-STING pathway. Mechanistically, Rv3248c bindsTANK-binding kinase 1 (TBK1) and promotes its ubiquitination-mediatedproteasomal degradation. The N-terminal region of Rv3248c (amino acids1–134) is required for TBK1 interaction and IFN-I inhibition.These findings identify a previously uncharacterized mechanism bywhich <em>M. tb</em> dampens the IFN-I response by targetingTBK1, highlighting Rv3248c as a contributor to pathogenesis and apotential therapeutic target.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 10","pages":"3385–3397"},"PeriodicalIF":4.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153071","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":"Antimicrobial Peptoids Show Potent Antifungal Activity against Candidozyma (Candida) auris In Vivo and Broad-Spectrum Activity In Vitro against Other Candida Species","authors":"Lisa K. Ryan,&nbsp;Isabella M. Griffiths,&nbsp;Uyen Emily Do,&nbsp;Denny Gao,&nbsp;Erika L. Figgins,&nbsp;Kristian Sørensen,&nbsp;Jennifer S. Lin,&nbsp;Natalia Molchanova,&nbsp;Kent Kirshenbaum,&nbsp;Annelise E. Barron,&nbsp;Gill Diamond","doi":"10.1021/acsinfecdis.6c00525","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00525","url":null,"abstract":"<p>Invasive candidiasis is a serious fungal infection causedby <em>Candida</em> species that can enter the bloodstreamand affectmajor organs, particularly in immunocompromised patients. Developmentof resistance to standard antifungal therapies, especially with <em>C</em>. <em>auris</em>, has become a major public healthissue. While antimicrobial peptides such as the human cathelicidin,LL-37, could represent a possible therapeutic strategy, they are ofteninactivated when delivered systemically. One alternative therapeuticstrategy is antimicrobial peptoids. We studied <em>in vitro</em> activity of three peptoid compounds, oligomers of <em>N</em>-substituted glycines, which mimic the activity of LL-37. Our aimwas to establish these peptoid compounds as a potential treatmentof invasive candidiasis and compare them to LL-37′s antifungalactivity. <em>In vitro</em>, LL-37 did not exhibit antifungalactivity (MIC &gt; 64) against all <em>C</em>. <em>auris</em> strains and three species of <em>Candida</em>. In contrast,three peptoids were tested against ten <em>C</em>. <em>auris</em> strains and six other <em>Candida</em> speciesand showed good activity. MICs measured as low as 4 μg/mL forTM5 against <em>C</em>. <em>auris</em> strain 381.Mechanistic studies using TEM and fluorescent confocal microscopyof peptoids against <em>C</em>. <em>auris</em> clinicalisolates showed membrane disruption and consolidation of organelles.Peptoids TM4 and TM5 showed strong synergistic effects with fluconazoleand caspofungin, and amphotericin B. Serial daily passage of TM4 andTM5 at sub-MIC concentrations showed no resistance developing forup to 3 weeks. Fungicidal kinetics revealed complete killing of fungalcolonies after around 1 h. A systemic candidiasis mouse model treatedsubcutaneously with TM5 3 h after <em>C</em>. <em>auris</em> infection resulted in clearing of infection, indicated by colonyforming units (cfu) per gram of kidney, at 24 h with the 5 mg/kg dose.This demonstrates that antimicrobial peptoids are active systemicallyand have potential to be an antifungal treatment for candidemia, particularlyas an alternative therapy for resistant strains.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 10","pages":"3462–3471"},"PeriodicalIF":4.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153144","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":"From Soil to Shelf: Teixobactin at Ten─Mechanism, SAR, and the Road to Clinical Application","authors":"Renaud Binette,&nbsp;Evelyne Lacasse,&nbsp;François Malouin,&nbsp;Pierre-Luc Boudreault","doi":"10.1021/acsinfecdis.6c00389","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00389","url":null,"abstract":"<p>The discovery of teixobactin in 2015 was a landmark inthe fightagainst antimicrobial resistance, introducing a novel antibiotic scaffoldwith a unique mechanism of action. Isolated from the previously unculturablesoil bacterium <em>Eleftheria terrae</em> usingthe innovative iChip technology, teixobactin initially showed theremarkable ability to kill pathogens without apparent developmentof resistance. Over the past decade, intensive research has unraveleda complex mode of action: teixobactin dual-targets the essential cellwall precursors Lipid II and Lipid III, then triggers a cascade ofself-assembly into amyloid-like fibrils on bacterial membranes, sequesteringthese precursors and lysing the cell. Commemorating its 10th anniversary,this review provides a comprehensive analysis of teixobactin’sjourney. We examine key structure–activity relationships (SAR)derived from the synthesis of numerous analogs that identified criticalresidues and moieties required for activity and led to promising derivativecompounds. At the same time, the road from soil to clinic has beenmarked by challenges. The very property that underlies teixobactin’spotent mechanism, its tendency to aggregate, also poses significantformulation problems, a “potency-formulation paradox.”Furthermore, the initial resistance-proof promise has been toned downby conflicting studies: some confirm an exceptionally high barrierto resistance, while others raise concerns about rapid adaptationand cross-resistance. On top of these scientific challenges are theeconomic and regulatory barriers that affect antibiotic developmenttoday. In sum, this review synthesizes a decade of research, framingteixobactin not only as a promising antibiotic candidate but alsoas an illuminating case study of the scientific, manufacturing, andeconomic challenges in bringing new antimicrobials to patients inthe 21st century.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 10","pages":"3280–3295"},"PeriodicalIF":4.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153174","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":"Targeting G3BP1-Mediated Stress Granules to Suppress SARS-CoV-2 Replication","authors":"Rukayat Aromokeye,&nbsp;Lisha Kuang,&nbsp;Martha Ackerman-Berrier,&nbsp;Savio Cardoza,&nbsp;Cameron Holberg,&nbsp;Megan Carver,&nbsp;Chunlong Ma,&nbsp;Anil Mathew Tharappel,&nbsp;Hongmin Li,&nbsp;Lei Wang,&nbsp;Gregory R. J. Thatcher,&nbsp;Haining Zhu","doi":"10.1021/acsinfecdis.5c01026","DOIUrl":"10.1021/acsinfecdis.5c01026","url":null,"abstract":"<p>Stress granules (SGs) are cytoplasmic, membraneless assembliesof proteins and RNAs that transiently form in response to cellularstress. Dysregulation of SGs has been associated with cancer, neurodegeneration,and viral infection. GTPase-activating protein SH3 domain-bindingprotein 1 (G3BP1) is a central SG component that regulates granuleassembly and dynamics through protein-RNA and protein–proteininteractions (PPIs). During viral infection, SGs can be hijacked toenhance viral replication and suppress host defense. In this study,we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)nucleocapsid protein (N) binds G3BP1 and localizes to G3BP1-positiveSGs in infected cells. We hypothesize that small-molecule ligandstargeting G3BP1 can disrupt the G3BP1-N interaction and reduce viralreplication. To test this, we developed a robust, miniaturized, 384-welltime-resolved fluorescence resonance energy transfer (TR-FRET) assayfor high-throughput screening (HTS). Screening a library of 2560 FDA-approveddrugs yielded 17 hits. Subsequent counterscreening, validation, andbiophysical binding studies identified 7 PPI inhibitors with IC₅₀ values ranging from 0.8 to 31 μM. In cell-based assays,two compounds─dexlansoprazole and citalopram─disruptedthe G3BP1-N interaction with minimal cytotoxicity. Both compoundsshowed antiviral activity in human lung epithelial cells infectedwith either the WA strain or an Omicron (BA.1) strain of SARS-CoV-2.This work establishes a strategy to modulate SGs by targeting a host–virusPPI, highlighting G3BP1 as a potential therapeutic node for antiviralintervention.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 10","pages":"3322–3334"},"PeriodicalIF":4.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643364","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":"Bacterial Aminopeptidase-Activated Peptide Prodrug Enables Species-Selective Targeting of Pseudomonas aeruginosa","authors":"Qingtian Gong,&nbsp;Silvia Synowsky,&nbsp;Aisling Lynch,&nbsp;John R. F. B. Connolly,&nbsp;Neeladri Sekhar Roy,&nbsp;Sally L. Shirran,&nbsp;Megan Bergkessel,&nbsp;Marc Devocelle,&nbsp;Clarissa M. Czekster","doi":"10.1021/acsinfecdis.6c00281","DOIUrl":"10.1021/acsinfecdis.6c00281","url":null,"abstract":"<p><em>Pseudomonas aeruginosa</em> is an adaptableorganism,frequently found in chronic infections, and for which antimicrobialresistance is a growing concern. Therefore, there is an urgent needfor alternative therapeutic strategies. Cationic antimicrobial peptides(AMPs) offer potent bactericidal activity but suffer from limitedselectivity and potential host toxicity. To enhance species-specifictargeting, we designed two prodrug variants of the AMP D-Bac8C^Leu2,5─EEEE-D-Bac8C^Leu2,5 and ELEG-D-Bac8C^Leu2,5─engineered for activation by the <em>P. aeruginosa</em> extracellular aminopeptidase PaAP. While both prodrug motifs effectivelyneutralized the positive charge of D-Bac8C^Leu2,5 and preventedDNA–peptide complex formation, EEEE-D-Bac8C^Leu2,5 showed negligible antimicrobial activity due to slow and incompleteactivation. In contrast, ELEG-D-Bac8C^Leu2,5 underwent rapidPaAP-mediated activation, restoring bactericidal activity in planktoniccultures and biofilms. PaAP contributed significantly to completeprodrug activation, particularly within biofilms, where the accumulationof partially activated intermediates correlated with biphasic killingkinetics. The prodrug showed reduced activity against other ESKAPEEpathogens, demonstrating selective activation by <em>P. aeruginosa</em>. Experiments selecting resistant bacteria revealed distinct mutationsin lipopolysaccharide biosynthesis pathways for D-Bac8C^Leu2,5 and the prodrug, with limited cross-resistance. These findings establishaminopeptidase-activated AMP prodrugs as a promising approach forspecies-selective antimicrobial therapy and highlight the feasibilityof exploiting bacterial enzymes for controlled antimicrobial peptideactivation.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3092–3103"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785433","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":"Molecular Architecture and Catalytic Mechanisms of Class D Carbapenemases: Insights into Antibiotic Resistance and Carbapenem Design","authors":"Clyde A. Smith,&nbsp;Marta Toth,&nbsp;Nichole K. Stewart,&nbsp;Sergei B. Vakulenko","doi":"10.1021/acsinfecdis.6c00611","DOIUrl":"10.1021/acsinfecdis.6c00611","url":null,"abstract":"<p>The β-lactam class of antibiotics remains indispensablefortreating bacterial infections, yet their effectiveness is increasinglycompromised by the emergence of carbapenem-hydrolyzing class D β-lactamases,the principal mechanism of carbapenem resistance in <em>Acinetobacter baumannii</em> and an important contributorto resistance in Enterobacterales. This review focuses on the structuralbiology and enzymatic mechanisms of these enzymes, with particularemphasis on the post-translationally carboxylated Lys73 and the solvent-restrictedpocket that encloses this residue. This pocket maintains the lysinein its catalytically essential carboxylated state, enabling it tofunction as the general base during both acylation and deacylation.A unique gating mechanism enables the entry of a deacylating waterinto the catalytic lysine pocket via the opening of a hydrophobiccap induced by the 6α-hydroxyethyl group of the carbapenem followingacylation of the enzyme. These insights provide a mechanistic frameworkfor the development of next-generation therapeutics capable of overcomingcarbapenem resistance. Recently designed carbapenem derivatives perturbcarboxylation of the catalytic lysine or disrupt proper positioningof the catalytic water in the active site, which severely impairsdeacylation and results in potent inhibition of CHDLs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"2965–2984"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943859","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":"Esculentin-1a Derived Peptides Potentiate Ceftazidime Activity against Multidrug-Resistant KPC-Producing Klebsiella pneumoniae","authors":"Dania Al Ismail,&nbsp;Carlo Vetrano,&nbsp;Luisa Torrini,&nbsp;Maria Rosa Loffredo,&nbsp;Eeva Tortellini,&nbsp;Alessandra Oliva,&nbsp;Bruno Casciaro,&nbsp;Matteo Rossi,&nbsp;Alessandra Carattoli,&nbsp;Maria Luisa Mangoni","doi":"10.1021/acsinfecdis.6c00366","DOIUrl":"10.1021/acsinfecdis.6c00366","url":null,"abstract":"<p>Carbapenemase-producing <em>Klebsiella pneumoniae</em> representsa major clinical threat due to the multidrug-resistant phenotype ofthis Gram-negative bacterium and to the limited available therapeuticoptions. Currently, antimicrobial peptides are regarded as promisingcandidates for the development of novel anti-infective strategies.In this study, the antimicrobial activity of the frog skin-derivedantimicrobial peptide Esc(1-21) and its three analogs, an Aib-containingpeptide and two variants bearing <span>d</span>-amino acids (i.e., thediastereomer Esc(1-21)-1c and [Aib⁸]-Esc(1-21)-1c isoform),was evaluated against a panel of clinical carbapenemase-producing <em>Klebsiella pneumoniae</em> isolates. In addition, the abilityof these <span>d</span>-amino acid-containing peptides to potentiate theeffectiveness of ceftazidime, a widely used third-generation cephalosporinfor treatment of severe Gram-negative bacterial infections, was investigated.Mechanistic analyses revealed that Esc(1-21)-1c promotes outer membranepermeabilization, thereby facilitating ceftazidime entry into theperiplasmic space. Notably, the peptide/ceftazidime combination treatmentresulted in enhanced outer membrane destabilization and increasedcytoplasmic membrane perturbation compared to the peptide alone. Thesefindings support a self-reinforcing mechanism in which ceftazidime-mediatedcell wall damage further destabilizes the bacterial envelope, promotingadditional peptide uptake and amplifying cytoplasmic membrane disruption.Time–kill assays confirmed the superior bactericidal activityof the peptide/ceftazidime combination compared to either agent usedalone. Importantly, no outer membrane perturbation was observed ina strain lacking a synergistic response, suggesting that membranesusceptibility is a key determinant of this cooperative interaction.Overall, these results highlight the potential of Esc-derived peptidesas adjuvants capable of restoring β-lactam efficacy againstmultidrug-resistant carbapenemase-producing <em>Klebsiella pneumoniae</em>, offering a promising strategy to combat antimicrobial resistance.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3169–3178"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943904","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":"Exploring the Pyrimidine Scaffold for the Development of SARS-CoV-2 Mpro Inhibitors","authors":"Salvatore Nieddu,&nbsp;Giuseppe Ruggieri,&nbsp;Riccardo De Santis,&nbsp;Paolo Malune,&nbsp;Elisa Patacchini,&nbsp;Valentina Noemi Madia,&nbsp;Francesco Saccoliti,&nbsp;Antonella Messore,&nbsp;Laura Zarbo,&nbsp;Angela Corona,&nbsp;Donatella Amatore,&nbsp;Giorgia Grilli,&nbsp;Alessandra Amoroso,&nbsp;Florigio Lista,&nbsp;Enzo Tramontano,&nbsp;Roberta Costi,&nbsp;Roberto Di Santo,&nbsp;Francesca Esposito","doi":"10.1021/acsinfecdis.6c00583","DOIUrl":"10.1021/acsinfecdis.6c00583","url":null,"abstract":"<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)isstill a major public health issue, even today. Among the SARS-CoV-2nonstructural proteins, the main protease (M^pro) playsa critical role in viral polyprotein processing and is therefore indispensablefor viral replication. For this reason, it represents one of the mostpromising therapeutic targets for the development of antiviral agentsagainst SARS-CoV-2. Currently, only one protease antiviral agent (nirmatrelvir)has received emergency approval for COVID-19 treatment, the diseasecaused by SARS-CoV-2 infection. However, the emergence of viral mutationsmay compromise its efficacy, highlighting the urgent need to developnew, safe, and effective protease antiviral agents. In the presentwork, we designed and synthesized new SARS-CoV-2 M^pro small-moleculeinhibitors endowed with a pyrimidine scaffold. A series of derivativeswere evaluated in both biochemical and cell-based assays to assesstheir antiviral efficacy, with some of them being able to inhibitthe SARS-CoV-2 M^pro activity and to suppress viral replication.Docking studies were confirmed by site-directed mutagenesis, and themechanism of action of the most promising compound was elucidated.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3253–3264"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943925","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":"Biochanin A Activates Mitochondrial UPR to Protect the Host against Pathogenic Bacterial Infection through the Conserved Transcription Factor ATFS-1/ATF5","authors":"Qiuyu Song,&nbsp;Yi Xiao,&nbsp;Xin Xiao,&nbsp;Fang Liu","doi":"10.1021/acsinfecdis.6c00007","DOIUrl":"10.1021/acsinfecdis.6c00007","url":null,"abstract":"<p>Biochanin A (BCA) is a natural isoflavone found in chickpeasandsoybeans. Although its biological activity is well established, therole of BCA in anti-infective immunity has not yet been fully elucidated.In this study, we demonstrated that BCA exploited the transcriptionfactor ATFS-1 to trigger the mitochondrial unfolded protein response(UPR^mt). In <em>Caenorhabditis elegans</em> (<em>C. elegans</em>), BCA increased resistanceto <em>Pseudomonas aeruginosa</em> (<em>P. aeruginosa</em> PA14) and other pathogens in a dosage-dependentmanner by reducing the intestinal bacterial load rather than directlyinhibiting bacterial proliferation. By screening classical signalingpathways, we found that the BCA-mediated protective effect was entirelydependent on the <em>atfs-1</em> gene, as BCA induced thenuclear translocation of ATFS-1 and upregulated UPR^mt andimmune effector factors. Notably, this mechanism was evolutionarilyconserved. In a mouse model, BCA dose-dependently increased survivalrates, reduced bacterial load in the lungs, and upregulated the expressionof ATF5 (the mammalian homolog of ATFS-1) and mitochondrial chaperoneproteins. This study is the first to reveal a cross-species conservedlink between BCA, the mitochondrial stress response, and the hostimmune system, providing a promising therapeutic target for the managementof clinical bacterial infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3019–3027"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943936","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":"In Vitro and In Vivo Activity against Staphylococcus aureus and Pharmacokinetic Evaluation of a Novel Pleuromutilin Candidate","authors":"Feifei Zhao,&nbsp;Xinyue Luo,&nbsp;Tingting Zhang,&nbsp;Honghao Huang,&nbsp;Yizhen Zhu,&nbsp;Wanxin Lin,&nbsp;Sujuan Wu,&nbsp;Youzhi Tang,&nbsp;Zhenling Zeng","doi":"10.1021/acsinfecdis.6c00558","DOIUrl":"10.1021/acsinfecdis.6c00558","url":null,"abstract":"<p><em>Staphylococcus aureus</em> infectionspose a serious threat to public health, exacerbated by antimicrobialresistance and the limited pipeline of novel agents. Pleuromutilin,a natural antibiotic, provides a promising scaffold for developingnew antibacterial agents via structural modification. To overcomethe poor druggability of the lead compound amphenmulin (APM), we designedand synthesized a novel derivative, <strong>Pleuro2–4</strong>.This derivative exhibited potent <em>in vitro</em> activityagainst <em>S. aureus</em>, with efficacy comparableto valnemulin and superior to tiamulin. Molecular docking suggestedfavorable interactions with the bacterial ribosome, while scanningelectron microscopy revealed morphological alterations associatedwith impaired cell division. Pharmacokinetics in mice revealed dose-dependentoral bioavailability (21.28% to 70.13%) and rapid metabolism to APM. <strong>Pleuro2–4</strong> significantly reduced bacterial loads ina dose-dependent manner and alleviated histopathological damage ina neutropenic murine thigh infection model. Collectively, <strong>Pleuro2–4</strong> exhibited improved oral exposure and bioavailability with potentantibacterial efficacy and favorable pharmacokinetic properties, warrantingfurther pharmacokinetic/pharmacodynamic and efficacy studies in targetspecies.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3230–3240"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943945","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}