ACS Infectious Diseases最新文献

{"title":"Antimicrobial Peptides and Biofilms: From Molecular Interactions to Therapeutic Control","authors":"Jayita Ghosh,&nbsp;Saikat Deb,&nbsp;Moumita Jana,&nbsp;Srirupa Mukherjee,&nbsp;Pushpanjali Singh,&nbsp;Kausik Dey,&nbsp;Sudatta Maity,&nbsp;Srikanta Pal,&nbsp;Samya Sen","doi":"10.1021/acsinfecdis.6c00118","DOIUrl":"10.1021/acsinfecdis.6c00118","url":null,"abstract":"<p>Therising problem of antimicrobial resistance (AMR), further complicatedby the resilience of bacterial biofilms, calls for the discovery ofnew therapeutic strategies. Bacteria residing in biofilms rely onextracellular polymeric substance (EPS) scaffolds, quorum sensing(QS) circuits, and metabolic dormancy to protect themselves againststandard antibiotics. Antimicrobial peptides (AMPs) have recentlybeen recognized as a promising new class of antimicrobials, exploitingmechanisms of action that circumvent established resistance mechanisms.This review offers a comprehensive overview of AMPs as antibiofilmagents, integrating basic molecular principles with translationalapplications. We discuss the critical challenges imposed by the biofilmenvironment and demonstrate how both natural and designed AMPs overcomethese barriers by disrupting EPS structure, quenching QS communication,and killing metabolically dormant persister cells. In addition totheir use as monotherapies, we assess the synergistic benefits ofinnovative AMP-antibiotic combinations, nanoparticle-AMP conjugates,and surface-functionalized coatings that aim to improve the stabilityand therapeutic index of AMPs. Moreover, this review also points tothe cutting-edge field of peptide engineering, where we emphasizethe importance of artificial intelligence, machine learning, and multiomicsapproaches to expedite the in silico design of synthetic peptides.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2416–2437"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366161","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":"Enhanced Respiratory Electron Dissipation by Immunometabolites Promotes Mycobacterial Biofilm Longevity","authors":"Kaushik Poddar,&nbsp;Gunjan Tripathi,&nbsp;Snehal V. Khairnar,&nbsp;Stuti Srivastav,&nbsp;Amitesh Anand","doi":"10.1021/acsinfecdis.6c00483","DOIUrl":"10.1021/acsinfecdis.6c00483","url":null,"abstract":"<p>Mycobacterial species inhabit diverse ecological nichesand frequentlyadopt a biofilm lifestyle, including within host environments, wherethis organization critically influences the persistence and pathophysiologicaloutcomes. Here, using <em>Mycobacterium smegmatis</em>, wedemonstrate that nitrate, a host-derived immunometabolite, markedlyextends the biofilm lifespan. Mechanistically, nitrate sustains respiratoryactivity and suppresses the induction of the dormancy response. Thiseffect is accompanied by the maintenance of intracellular redox balance,consistent with enhanced electron dissipation. Importantly, fumarate,a distinct host-relevant metabolite capable of facilitating electrondissipation, recapitulates this phenotype, indicating that the observedbiofilm longevity is not limited to nitrate but instead is linkedto the availability of alternative electron sinks. Together, our findingsestablish that the electron dissipation capacity is a key determinantof respiratory homeostasis and biofilm persistence in mycobacteria.We report a similar phenotype for <em>M. abscessus</em>, anontuberculous opportunistic pathogen. These results highlight respiratoryflexibility as a central adaptive axis through which mycobacteriaexploit host metabolic cues to prolong survival.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2593–2600"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262403","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":"Temporin-Derived Peptides Protect Mice against Enterohemorrhagic Escherichia coli O157:H7 Infection by Inhibiting Inflammation and Enhancing the Intestinal Epithelial Barrier","authors":"Jing Chen,&nbsp;Ruiying Zhu,&nbsp;Shangjun Jiang,&nbsp;Zhiju Xue,&nbsp;Wenhuan Deng,&nbsp;Yining Wang,&nbsp;Shuangshuang Wei,&nbsp;Junchen Lyu,&nbsp;Wenting Hu,&nbsp;Yanting Song,&nbsp;Rong Wang,&nbsp;Yingxia Zhang","doi":"10.1021/acsinfecdis.6c00158","DOIUrl":"10.1021/acsinfecdis.6c00158","url":null,"abstract":"<p>Intestinal inflammation can destroy the integrity ofthe intestinalbarrier and disrupt immune homeostasis, increasing the risks of developingfatal diseases. Enterohemorrhagic <em>Escherichia coli</em> (EHEC) O157:H7, a prominent pathogen primarily transmitted throughcontaminated food, is known to trigger intestinal inflammation andsubsequent infections. Temporin-GHbK (GHbK) and temporin-GHb3K (GHb3K),derived from temporin-GHb of <em>Hylarana guentheri</em>, were synthesized and demonstrated antimicrobial and anti-biofilmactivities against EHEC <em>in vitro</em>. They also exhibitedefficacy in preventing EHEC infection <em>in vivo</em>. GHbKand GHb3K significantly decreased the disease activity index (DAI)in EHEC-infected mice in comparison with the untreated model group.The derived peptides exhibited barrier-protective effects by preservingstructural integrity, reducing inflammatory infiltrates in the intestinalepithelium, and maintaining gut microbiota diversity. Taken together,GHbK and GHb3K exhibit promising anti-inflammatory and anti-infectionpotential against EHEC infection. These findings lay a foundationfor exploring the application of antibacterial peptides in the treatmentof EHEC infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2663–2680"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148402895","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":"Development of Semisynthetic Blasticidin S Analogs with Potent and Fast-Killing Antimalarial Activity","authors":"Katherine R. Fike,&nbsp;Cole Gannett,&nbsp;Anastazja M. Kiselka,&nbsp;Kateland Tiller,&nbsp;Toheeb Ajasa,&nbsp;James Weger-Lucarelli,&nbsp;Anne M. Brown,&nbsp;Andrew N. Lowell,&nbsp;Michael Klemba","doi":"10.1021/acsinfecdis.6c00362","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00362","url":null,"abstract":"<p>Protein synthesis represents an attractive target spacefor thedevelopment of antimalarials with novel modes of action. Natural-productinhibitors of the eukaryotic 80S ribosome can have potent antimalarialactivity but are often poorly selective due to mammalian cytotoxicity.Blasticidin S is a microbially produced natural product that broadlyinhibits prokaryotic and eukaryotic protein synthesis by binding tothe ribosomal peptidyl transferase center. In this study, we exploredthe potential for improving the antimalarial potency and selectivityof the blasticidin S scaffold with semisynthetic analogs that aremodified at the C6’ and C4 sites. The two best analogs were2 orders of magnitude more potent than blasticidin S against <em>Plasmodium falciparum</em> drug-sensitive and -resistantlines while displaying low cytotoxicity toward mammalian cells. Theseanalogs exhibited improved kinetics of inhibition of protein synthesisin cultured parasites and arrested asexual development after the onsetof plasmodial surface anion channel expression, a transporter requiredfor nutrient acquisition and blasticidin S uptake. They also exhibiteda dramatically improved speed of killing over blasticidin S. Moleculardocking analysis revealed that these analogs are able to form moreinteractions with the <em>P. falciparum</em> ribosomal peptidyl transferase center than is blasticidin S, whichis consistent with their increased potency. Together, these studiesdemonstrate the feasibility of generating blasticidin S analogs withpotent antimalarial activity and provide a roadmap for further development.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2788–2798"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729442","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":"Clinically Relevant Altered Antibiotic Responses and Mechanisms of β-Lactam Sensitization of MRSA in Cystic Fibrosis Artificial Sputum","authors":"Tyler J. Hamelin,&nbsp;Ali Molaeitabari,&nbsp;Marc R. MacKinnon,&nbsp;Tanya E. S. Dahms,&nbsp;Omar M. El-Halfawy","doi":"10.1021/acsinfecdis.6c00319","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00319","url":null,"abstract":"<p><em>Staphylococcus aureus</em> isthe mostcommon bacterial pathogen affecting pediatric patients with cysticfibrosis (CF), a genetic disorder that causes thick mucus buildupin the lungs, providing a scaffold for chronic infections. Antibiotictreatment is typically guided by standard <em>in vitro</em> antimicrobial susceptibility testing (AST) in Mueller-Hinton broth(MHB), which does not represent the infection site in CF lungs. Notably,discordances between AST predictions and antibiotic therapeutic outcomeshave been reported in up to 50% of CF cases. To address this gap,we conducted ASTs against methicillin-resistant <em>S. aureus</em> (MRSA) in CF sputum-mimetic media comparedwith MHB, demonstrating ≥ 4-fold discordances across four ofnine antibiotic classes. Most significantly, we observed unexpectedβ-lactam sensitization of MRSA strains (up to 128-fold) in CFsputum-like media, crossing the clinical breakpoint, suggesting thisshift may alter therapeutic outcomes. Genome-wide screens and follow-upassays revealed underlying cell envelope remodeling and alterationsto cell envelope stress responses. On the other hand, mucin bindingto daptomycin may have led to an apparent 8-fold increase in resistanceto this antibiotic in one of the CF sputum-like media. Overall, ourAST results in CF sputum-mimetic conditions provide insights intobacterial responses during CF infections. Importantly, they suggestβ-lactams may be effective in treating MRSA infections in CFpatients, warranting further investigation in relevant <em>in vivo</em> systems.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2763–2777"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729629","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":"A Modular T4 Phage-Based Nanoparticle Displaying Multiepitopes Provides Cross-Serotype Protection against Streptococcus suis in Mice and Swine","authors":"Guosheng Chen,&nbsp;Shiting Ni,&nbsp;Jingya Guo,&nbsp;Lijun Yang,&nbsp;Yuying Li,&nbsp;Zhengnan Yuan,&nbsp;Yongyi Zhang,&nbsp;Yanyan Zhang,&nbsp;Huanchun Chen,&nbsp;Pan Tao,&nbsp;Chen Tan","doi":"10.1021/acsinfecdis.6c00464","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00464","url":null,"abstract":"<p><em>Streptococcus suis</em> isan importantzoonotic pathogen that is widely distributed in the global swine industry.Our previous studies demonstrated that the bacterial elongation factorIF-2 protein provides protection against <em>S. suis</em> infectionin mice. On this basis, the T-cell and B-cell epitopes of IF-2 werepredicted and concatenated to generate the IF2–1 and IF2–2polypeptides. We successfully constructed IF2–1-T4 and IF2–2-T4nanoparticles on the basis of the IF-2 protein via the T4 <em>in vivo</em> assembly platform. Both IF2–1-T4 and IF2–2-T4nanoparticles exhibited superior immunoprotective efficacy comparedwith IF-2 in mouse models, regardless of the presence of adjuvants.Among them, IF2–2-T4 showed the strongest protection and demonstratedthe potential to induce cross-protection against multiple <em>S. suis</em> serotypes, providing a promising strategy for thedevelopment of broad-spectrum <em>S. suis</em> vaccines. Furthermore,this study systematically evaluated the immunoprotective efficacyof a recombinant T4 phage-based vaccine in a swine model and comparedthe effects of intramuscular and needle-free immunization routes.Collectively, these results establish a foundation for the applicationof T4 nanoparticle-based vaccines in swine and offer new insightsinto the design of cross-protective vaccines against <em>S. suis</em> and other bacterial pathogens.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2838–2852"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729855","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":"Label-Free Liquid Crystal-Based Dielectric Genosensor for Infectious Bacterial Detection","authors":"Rohit Kumar,&nbsp;Gajjala Sumana,&nbsp;Sudesh Yadav,&nbsp;Seema Sood,&nbsp;Shyam S. Pandey,&nbsp;Hirofumi Tanaka,&nbsp;Rajesh","doi":"10.1021/acsinfecdis.6c00192","DOIUrl":"10.1021/acsinfecdis.6c00192","url":null,"abstract":"<p>A dielectric liquid crystal (LC)-basedgenosensor was developedfor the detection of the bacterium, <em>Neisseria gonorrhoeae</em>, a sexually transmitted pathogen. The LC-dielectric sensing platformwas fabricated by biomolecular immobilization of an <em>N. gonorrhoeae-</em>specific oligonucleotide probe (ssDNA_probe) on premodified electrodes of the LC cell for the detectionof genomic DNA of <em>N. gonorrhoeae</em> (DNA_N.g) using a low-frequency dielectric transduction mechanism.The sensing mechanism is based on dielectric spectroscopic analysisat 100 Hz, revealing a significant increase in relative permittivitycaused by the random orientation of 5CB LC molecules at the LC-electrodeinterface due to DNA hybridization (ssDNA_probe-ssDNA_N.g) at the electrode surface. The LC-dielectric genosensordemonstrated a linear change in relative permittivity (Δε′)response over a wide range of 1 pM to 100 nM DNA_N.g, witha low detection limit (LOD) down to 0.5 pM and a sensitivity of Δε′= 9.38 per decade of DNA_N.g. The dielectric sensing performanceof the LC genosensor was compared to that of optical transductionobserved under polarized optical microscopy and was found to be 20times better for low-level detection than the optical LOD of 10 pMDNA_N.g. Specificity studies were performed with potentialinterferents of non-<em>N. gonorrhoeae</em><em>Neisseria</em> species, such as <em>Neisseria sicca</em>, <em>Neisseria mucosa</em>, and <em>Neisseria meningitidis</em>, and other bacterial specieslike <em>Escherichia coli</em>, <em>Pseudomonas aeruginosa</em>, and <em>Staphylococcus aureus</em>. The observation of insignificant dielectricresponse with the potential interferents demonstrated the good selectivityof the LC genosensor for <em>N. gonorrhoeae</em>. The comparatively higher sensitivity of dielectric transductionover the optical one indicates the suitability of the LC-dielectricgenosensor as a promising tool for the sensitive detection of <em>N. gonorrhoeae</em> for improved diagnostic capabilitiesand management.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2695–2702"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589252","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":"Bonnie Bassler: From Eavesdropping to Rewriting Our Understanding of Bacterial Communication","authors":"Laura C. Miller Conrad,&nbsp;Sampriti Mukherjee,&nbsp;Jayanta Haldar","doi":"10.1021/acsinfecdis.6c00664","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00664","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2409–2412"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729467","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":"Structure–Activity Analysis of the Competence Stimulating Peptide-1 in Streptococcus mitis","authors":"Morgan M. Yeager,&nbsp;April K. Murray,&nbsp;Ripon C. Bhowmic,&nbsp;Clay P. Renshaw,&nbsp;Tahmina A. Milly,&nbsp;Yftah Tal-Gan","doi":"10.1021/acsinfecdis.6c00548","DOIUrl":"10.1021/acsinfecdis.6c00548","url":null,"abstract":"<p>Antibiotic-resistant bacteria are one of the greatestchallengesin modern medicine, as multidrug-resistant strains continue to outpacetraditional antibiotic development. Unlike conventional antibioticsthat promote resistance through selective pressure, quorum sensing-targetedtherapies disrupt bacterial communication systems that regulate, amongother traits, virulence, biofilm formation, and resistance acquirementthrough competence without directly killing the bacteria. In thisstudy we examined quorum sensing modulation in <em>Streptococcus mitis</em>, a commensal oral bacterium that has recentlybeen identified as an opportunistic pathogen capable of causing seriousinfections in immunocompromised individuals. The competence regulonquorum sensing system in <em>S. mitis</em> iscontrolled by the competence-stimulating peptide (CSP), which activatesthe histidine kinase receptor ComD to drive quorum sensing-regulatedprocesses. <em>S. mitis</em> strains can bedivided into different specificity groups, or pherotypes, based onthe CSP they produce and cognate ComD receptor. In this work we setout to define the molecular interactions that drive CSP1/ComD1 bindingand lead to ComD1 activation by conducting a systematic structure–activityanalysis of the <em>S. mitis</em>-CSP1 sequence.To this end, we synthesized and screened two <em>S. mitis</em>-CSP1 analog libraries: the first, an alanine scan to identify keyside-chain residues responsible for activity, and the second, a <span>d</span>-amino acid scan to evaluate the effect of side chain spatialorientation. Then, following the construction of a luminescence-based <em>S. mitis</em> NCTC 8033 quorum sensing reporter strain,we conducted reporter gene bioassays to gain insights into the structure–activityrelationship between <em>S. mitis</em>-CSP1and its cognate ComD1 receptor. Interestingly, our results revealedthat the glutamic acid-1-to-alanine analog (<em>S. mitis</em>-CSP1-E1A) had increased potency but lower efficacy, indicating partialagonist effects in <em>S. mitis</em> NCTC 8033,whereas the same glutamic acid-1-to-alanine substitution in CSPs fromother <em>Streptococcus</em> species, as wellas in a different <em>S. mitis</em> pherotypeproducing and responding to <em>S. mitis</em>-CSP2, has been reported to produce inhibitory analogs. These resultssuggest that the ComD1 receptor in <em>S. mitis</em> NCTC 8033 interacts with <em>S. mitis</em>-CSP1 differently than its homologues in other <em>Streptococcus</em> species, highlight the importance of species-specific studies, andcaution against overgeneralizing bacterial behavior within a givengenus. Overall, our work offers mechanistic insight into <em>S. mitis</em> quorum sensing signaling and lays a foundationfor the rational development of CSP-based tools to study and potentiallycontrol quorum sensing-regulated processes in streptococci.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2863–2873"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148496817","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":"Pre-Exposure to Cyclosporine A Primes Paracoccidioides brasiliensis to Evade Host Immunity","authors":"Filipe Nogueira Franco,&nbsp;Jean de Souza Lisboa Kozlowski,&nbsp;Nycolas Willian Preite,&nbsp;Coral Molist-Homs,&nbsp;Luiz Fernando de Oliveira,&nbsp;Ana Beatriz Furtado Rodrigues,&nbsp;João Henrique Dal Ponte Silva,&nbsp;Érica Borges Lima,&nbsp;Flávio Vieira Loures,&nbsp;Claudia Barbosa Ladeira de Campos","doi":"10.1021/acsinfecdis.6c00285","DOIUrl":"https://doi.org/10.1021/acsinfecdis.6c00285","url":null,"abstract":"<p>Paracoccidioidomycosis (PCM) is a systemic mycosis endemicto SouthAmerica caused by thermodimorphic fungi of the genus <em>Paracoccidioides</em>, particularly <em>P. brasiliensis</em>. Calcineurin inhibition by cyclosporineA (CsA) perturbs fungal thermodimorphism and growth. Here, we askedwhether pre-exposure of <em>P. brasiliensis</em> yeasts to CsA modulates host–pathogen interactions duringinfection. Mice infected with CsA-pre-exposed fungi exhibited significantlyreduced levels of pro- and anti-inflammatory cytokines, along withdecreased recruitment and activation of innate and adaptive immunecells at both time points. Although tissue inflammation and lesionareas were diminished, fungal burdens in lungs and liver were similarbetween groups. Importantly, yeasts recovered from lungs 72 h afterinfection with CsA-pretreated fungi displayed reduced <em>in vitro</em> colony growth, suggesting that prior CsA exposure induces a persistentslow-growth physiological state. This altered phenotype may impaireffective immune recognition and inflammatory activation. As hostimmunosuppression was excluded in the experimental design, fungus-intrinsicphenotypes consistent with transient calcineurin pathway inhibition:altered growth/morphogenesis and putatively modified PAMP exposurethat together blunt early immune activation. We interpret late-phasedifferences as downstream of these early pathway-dependent shiftsrather than as heritable reprogramming. Overall, pre-exposure to CsAmodulates <em>P. brasiliensis</em>–hostinteraction, dissociating tissue injury from fungal burden, highlightsthe role of calcineurin in fungal adaptation, and demonstrates howenvironmental exposure to bioactive compounds can influence fungalvirulence and disease outcomes.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 8","pages":"2727–2738"},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729522","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}