ACS Infectious Diseases最新文献

{"title":"Larval Exposure Rather than Adult Worm Burden Shapes Systemic and Mucosal Th2 Immunity in Ascaris suum Infected Pigs","authors":"Larissa Oser,&nbsp;Sara Roose,&nbsp;Ankur Midha,&nbsp;Josephine Schlosser-Brandenburg,&nbsp;Alexandra Laubschat,&nbsp;Zaneta D. Musimbi,&nbsp;Arkadi Kundik,&nbsp;Philipp Höfler,&nbsp;Christina S. Helm,&nbsp;Georg von Samson-Himmelstjerna,&nbsp;Peter Geldhof,&nbsp;Susanne Hartmann,&nbsp;Friederike Ebner","doi":"10.1021/acsinfecdis.6c00176","DOIUrl":"10.1021/acsinfecdis.6c00176","url":null,"abstract":"<p>Ascariasis is a prevalent parasitic infection in bothhumans andpigs, resulting in significant human morbidity and economic lossesin the porcine industry. Experimental infections are often studiedby mimicking natural settings, exposing the host to frequent, smalldoses (trickle infection) or by administering a single (bolus) doseof infective eggs. However, the impact of infection schemes and doseson the host immune response in<em>A. suum</em> infected pigs is still unclear. Using trickle and bolus infectionsand applying different doses, we found systemic GATA3+CD4+ T cellsand eosinophils increased dose-dependently during <em>A. suum</em> body migration, while CD4+ T cells that specificallyrecognize <em>A. suum</em> antigens showed noassociation with the infection dose. In contrast, all dose-dependentdifferences were resolved by 8–9 weeks post infection, whenadult worms were present. The results further showed that adult wormburden did not differ detectably across all groups, though a highintragroup variability was observed. Local type 2, germinal centerB cell, and Tfh cell responses were dose-dependent in bolus infectedanimals only. Our data suggest that the initial immune response generatedduring <em>A. suum</em> larval migration ispivotal in determining the fate of the antiparasite response and adultworm population. Moreover, our results indicate that the host canregulate the worm load independent of the infection dose and scheme.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3053–3067"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943924","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 Pathogen-Hopping Approach for the Identification of Compounds with Multistage Antischistosomal Activity","authors":"Malcolm G. Taylor,&nbsp;Priscilla Mendonca Matos Day,&nbsp;Kristin Lees,&nbsp;Nicola Caldwell,&nbsp;Josephine E. Forde-Thomas,&nbsp;Benjamin J. Hulme,&nbsp;Mary Evans,&nbsp;Kevin D. Read,&nbsp;Ian H. Gilbert,&nbsp;Karl F. Hoffmann,&nbsp;Beatriz Baragaña","doi":"10.1021/acsinfecdis.6c00446","DOIUrl":"10.1021/acsinfecdis.6c00446","url":null,"abstract":"<p>“Pathogen-hopping”is an approach in infectious diseaseresearch with potential to expedite drug discovery. This is done bytesting agents which are active against one or more pathogens in anew pathogen, exploiting the fact that orthologues of protein targetsessential for survival exist across different pathogens. In some cases,these compounds possess selectivity versus the human orthologue, furtheraiding the process. To identify new lead compounds for our schistosomiasisdrug discovery program, we adopted this approach by first mining theliterature to find antimalarial compounds which had not been evaluatedagainst <em>Schistosoma</em>. Next, a filtering process wasapplied to remove undesirable or potentially toxic compounds. Thetriaged set of compounds was then screened against <em>Schistosoma mansoni</em> schistosomula and adult worms. Two chemotypes displayedschistosomula and adult worm paralysis activity. Hit assessment wascompleted for one of these multistage actives to assess its potentialfor development as an antischistosomal treatment.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"2985–2994"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943755","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":"Phenotypic Effects of a Small Molecule CpxA Phosphatase Inhibitor on Uropathogenic Escherichia coli","authors":"Alexis M. Stoorza,&nbsp;Erin E. Carlson,&nbsp;Adam S. Duerfeldt","doi":"10.1021/acsinfecdis.6c00457","DOIUrl":"10.1021/acsinfecdis.6c00457","url":null,"abstract":"<p>Patients sufferingfrom Urinary Tract Infections (UTIs)are facedwith multidrug resistance and a lack of treatment options. An alternativestrategy to traditional bactericidal drug design is to disarm pathogenicbacteria by targeting the regulation of virulence factors. Small-moleculeCpxRA phosphatase inhibitor compound 26, hereafter referred to asCpx26, has shown efficacy in a murine UTI model; however, the impactof pharmacological modulation of CpxRA on bacterial physiology isundefined. Herein, we report the activity of Cpx26 in phenotypic assaysto provide insight into its mechanism of action and antivirulenceproperties. Cpx26 significantly inhibited swimming motility, biofilmformation, and adhesion to bladder epithelial cells at concentrations&gt;60-fold below its MIC. Combination with first-line UTI antibioticswas explored, and synergy was observed with trimethoprim/sulfamethoxazoleand fosfomycin, implying potential clinical benefit. This work highlightsthe potential of antivirulence therapies for prevalent infectionssuch as UTIs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"2995–3001"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943864","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":"Deciphering the Role of the Nonactive Site Ancillary Residues in Maintaining the Activity and Substrate Specificity of the OXA-232 β-Lactamase","authors":"Ajith Tejavath,&nbsp;Bayomi Biju,&nbsp;Aditya Prasad Panda,&nbsp;Diamond Jain,&nbsp;Chiranjit Chowdhury,&nbsp;Anindya Sundar Ghosh","doi":"10.1021/acsinfecdis.6c00512","DOIUrl":"10.1021/acsinfecdis.6c00512","url":null,"abstract":"<p>OXA-232, an OXA-48 - like carbapenemasestands among newly identifiedβ-lactamases that causes of the extensive of β-lactamresistance. While active-site residues are well characterized, thecontributions of conserved nonactive-site residues in exerting enzymaticactivity remain unexplored, limiting our understanding about the rolesof these residues in the overall OXA-232 function. To address thesegaps, the conserved residues S118, V120, L158, and D159 of OXA-232positioned adjacent to the active-site motifs and within the Ω-loopwere substituted with alanine. Substitutions of S118A and D159A renderedthe expressing cells susceptible to penicillins, cephalosporins, andcarbapenems, whereas the cells harboring OXA-232_V120A andOXA-232_L158A exhibited substrate-selective susceptibilitychanges. Kinetic analysis with purified proteins revealed the reductionin catalytic efficiency of all the mutants compared to wild-type protein.Though the L158A and D159A mutated proteins become deacylation-deficient,the mutations S118A and V120A exhibited selective acylation defectswithout trapping intermediates. It is evident from circular dichroismspectroscopy and molecular dynamics simulations that OXA-232_S118A, OXA-232_V120A, OXA-232_L158A and OXA-232_D159A nearly retained their secondary structures and compactness.Interestingly, bicarbonate supplementation partially rescued the lostactivities in soluble mutants, underscoring the carbamylation dependence.Taken together, these findings establish S118 and D159 as essentialfor core catalysis and structural integrity, with V120 and L158 modulatingsubstrate-specific turnover and orientation. The current study reappraisedthe mechanistic insights of OXA-48-like carbapenemases, providingsignificant resources in rationally designing future therapeuticsto combat carbapenem resistance.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3217–3229"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943908","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":"Second Generation of 2,2′-Di(indol-3-yl)ethanamines as Antileishmanial Agents: Phenotypic Hit Identification and Pharmacophore Studies","authors":"Gian Marco Elisi,&nbsp;Antonio Gkoutzamanis,&nbsp;Sara Maestrini,&nbsp;Cécile Exertier,&nbsp;Michela Eleuteri,&nbsp;Marina Naldi,&nbsp;Alessia Peluso,&nbsp;Miriam Gómez-Benmansour,&nbsp;Aurora Diotallevi,&nbsp;Michele Verboni,&nbsp;Laura Goracci,&nbsp;Manuela Bartolini,&nbsp;Giovanni Bottegoni,&nbsp;Paula Kiuru,&nbsp;Andrea Ilari,&nbsp;Luca Galluzzi,&nbsp;Simone Lucarini","doi":"10.1021/acsinfecdis.6c00079","DOIUrl":"10.1021/acsinfecdis.6c00079","url":null,"abstract":"<p>The urgent need fornew antileishmanial drugs persistsdue to resistanceand toxicity associated with current treatments. Although bisindolesrepresent a promising chemotype, our first-generation 2,2′-di(indol-3-yl)ethanamines,inspired by a natural marine alkaloid, displayed significant cytotoxicitydespite potent activity against <em>L. infantum</em>. To address this limitation, we designed and synthesized a second-generationseries in which the indole bromine substituents were removed, and <em>N</em>-methylation was prioritized as a strategy to mitigatecytotoxicity. Compounds <strong>1e</strong>, <strong>2b</strong>, <strong>2f</strong>, <strong>3d</strong>, and <strong>3e</strong> emerged as promising hits,exhibiting potent activity against <em>L. infantum</em> promastigotes (IC₅₀ = 0.6–3 μM) and markedlyimproved selectivity indices (SI = 11–66) in THP-1 cells. Thesecompounds retained efficacy in an <em>in vitro</em> infectionmodel, with <strong>1e</strong>, <strong>2b,</strong> and <strong>2f</strong> displayingIC₅₀ values below 10 μM against intracellular amastigotes.A pharmacophore model derived from URB1483 and <strong>2f</strong> wasgenerated to explore plausible mechanisms of action underlying theantileishmanial activity, with trypanothione reductase (TR) selectedas a possible biological target. While compound <strong>2f</strong> showedonly weak inhibition (IC₅₀ = 71 μM), this could providea starting point for the structure-based design of future antileishmanialagents. Preliminary ADME-related evaluations of <strong>1e</strong> and <strong>2f</strong> revealed improved aqueous solubility, alongside favorablechemical and metabolic stability specifically for <strong>1e</strong>.Consequently, while <strong>2f</strong> could be a new hit for a stillunderexploited target, compound <strong>1e</strong> emerges as the mostbalanced lead candidate for future development of antileishmanialderivatives.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3028–3042"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943867","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":"Mitophagy Increases Resistance against Infection of Pseudomonas aeruginosa through the PHB2/PARL/PGAM5/PINK1 Axis","authors":"Liumei Ye,&nbsp;Moluyu Wei,&nbsp;Yi Jian,&nbsp;Ruoyang Zhao,&nbsp;Jiaoxia Qin,&nbsp;Menghui Wu,&nbsp;Qihang Nie,&nbsp;Yanyan Zhang,&nbsp;Lilu Shi,&nbsp;Ming Wang,&nbsp;Min Wu,&nbsp;Ke Wang","doi":"10.1021/acsinfecdis.5c00894","DOIUrl":"10.1021/acsinfecdis.5c00894","url":null,"abstract":"<p><em>Pseudomonas aeruginosa</em> (<em>P.a</em>) isa common opportunistic pathogen causing seriousinfection and complications in diverse populations, especially underimmunodeficient conditions. Previous studies indicate that mitophagyactivation is related to multiple conditions and processes in thehuman body, including infectious diseases. It has been recently implicatedthat the PARL-PGAM5-PINK1 axis activates mitophagy, but its regulatoryrole in pneumonia is unclear. We hypothesize that mitophagy receptorPHB2 orchestrates an autophagic process through PARL and PGAM5 tolimit <em>P.a</em>. infection and inflammation. By knockingdown PHB2, we explored the regulatory role of mitophagy in <em>P.a</em> infection and evaluated the underlying mechanism ofthe PARL-PGAM5-PINK1 signals both in vitro and in <em>P.a</em> pneumonia mice. Our study also reveals that the critical factors,such as PARL and PINK1, may have potential for therapeutic targetingduring Pseudomonas infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3009–3018"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943873","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":"Tobramycin-Peptide Nucleic Acids Synergize with Polymyxin B and Other Bioactive Compounds to Inhibit Growth of Gram-Negative Bacteria","authors":"Sandra Story,&nbsp;Sarah Wicks,&nbsp;Sayantan Bhaduri,&nbsp;Alain S. Leutou,&nbsp;Dev P. Arya","doi":"10.1021/acsinfecdis.6c00322","DOIUrl":"10.1021/acsinfecdis.6c00322","url":null,"abstract":"<p>Antisense oligomersshow promise for the treatment of infectiousdiseases but face challenges as therapeutic agents due to limiteduptake in bacteria. Although cell-penetrating peptides can serve aseffective delivery vehicles, they may exhibit nonspecific effectsand can contribute to resistance development. Aminoglycoside-peptidenucleic acid (PNA) conjugates represent a complementary delivery strategythat leverages the intrinsic cationic and membrane-interacting propertiesof aminoglycosides to enhance cellular uptake. In this work, we synthesizedtobramycin-PNA (TOB-PNA) conjugates targeting the translation initiationregion of the acyl carrier protein gene (<em>acpP</em>) inEnterobacterales. Conjugation of TOB to PNA enhanced target-bindingstability, improved the inhibition of translation <em>in vitro</em>, and enhanced activity against Gram-negative bacteria. TOB-PNA activitywas further enhanced in combination with the outer membrane-permeabilizingantibiotic polymyxin B (PMB), leading to improved antibacterial activityagainst clinically relevant Gram-negative pathogens, including drug-resistantisolates. Resistance studies demonstrated that the TOB-PNA conjugate,both alone and in combination with PMB, maintains antibacterial activityover prolonged exposure, suggesting a higher barrier to resistanceevolution than conventional TOB treatment. Mammalian toxicity studiesin HEK293T cells showed IC₅₀ &gt; 100 μM. Morphologicalanalyses indicated that TOB-PNA treatment induces cellular stressand division abnormalities consistent with disruption of essentialmetabolic pathways, while PMB increased membrane permeability. Inaddition, TOB-PNA behaved synergistically with other compounds targetingdistinct cellular processes, including fatty acid biosynthesis (triclosan),folate metabolism (trimethoprim), and cell morphology (A22).</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3144–3158"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943901","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":"Biomaterials for Mitigating Infectious Diseases","authors":"Rachit Agarwal,&nbsp;Runhui Liu,&nbsp;Jayanta Haldar","doi":"10.1021/acsinfecdis.6c00748","DOIUrl":"10.1021/acsinfecdis.6c00748","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"2897–2899"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943932","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":"Mechanistic Roles of Conserved Active-Site Residues in OXA-48 Carbapenem Hydrolysis","authors":"Doris M. Taylor,&nbsp;Dignité Fabrice Ngango,&nbsp;Jiayi Fan,&nbsp;Suhyeorn Park,&nbsp;Banumathi Sankaran,&nbsp;B. V. Venkataram Prasad,&nbsp;Timothy Palzkill","doi":"10.1021/acsinfecdis.6c00562","DOIUrl":"10.1021/acsinfecdis.6c00562","url":null,"abstract":"<p>Carbapenem-hydrolyzing class D β-lactamasesarea major sourceof resistance to last resort β-lactam antibiotics. OXA-48 isa class D β-lactamase that hydrolyzes carbapenems through acatalytic mechanism involving a nucleophilic serine and a carboxylatedlysine general base. To define the contributions of conserved active-siteresidues to catalysis and substrate turnover, alanine substitutionswere introduced at key active site positions, followed by steady-stateand presteady-state kinetic analysis of mutant enzymes for imipenemand cephalothin hydrolysis. Mutations produced distinct effects, revealingroles in substrate acylation and deacylation reactions. Substitutionsat Val120, Trp157, and Leu158 cause the largest decreases in <em>k</em>_cat for both imipenem and cephalothin hydrolysis.It is known that deacylation is the rate-limiting step in carbapenemhydrolysis by OXA-48 and presteady-state kinetics analysis shows thatthe V120A and L158A substitutions further slow the deacylation reactionfor imipenem, reducing <em>k</em>_cat and <em>k</em>_cat/<em>K</em>_M values. Ourdata are also consistent with acylation being rate-limiting for cephalothinhydrolysis, with the V120A and L158A substitutions reducing substratebinding affinity and/or the acylation rate. Structural analysis indicatesthat the V120A enzyme has open water channel to the noncarboxylatedLys73 while the L158A enzyme is also open to water but has a carboxylatedLys73. Together, these results support a model in which conservedhydrophobic active-site residues optimize the geometric and electrostaticenvironment required for efficient carbapenem deacylation and turnover.These findings provide mechanistic insight into OXA-48 catalysis thatmay be exploited to design inhibitors targeting the enzyme.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3241–3252"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943943","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":"5-Carboxamide-Substituted Barbituric Acids: Promising Scaffolds for Drug Development against Mycobacterium tuberculosis","authors":"Henok A. Sahile,&nbsp;Bhuwan Awasthi,&nbsp;Jonas E. Olsen,&nbsp;Houria Afshar,&nbsp;Sung-Won Kim,&nbsp;Itay Amrom,&nbsp;Zohra Nikjo,&nbsp;Leah Rankine-Wilson,&nbsp;Wayne W. H. Law,&nbsp;Selvarani Vimalanathan,&nbsp;Clement K.M. Tsui,&nbsp;John L. Rubinstein,&nbsp;Brent D. G. Page,&nbsp;Yossef Av-Gay","doi":"10.1021/acsinfecdis.6c00420","DOIUrl":"10.1021/acsinfecdis.6c00420","url":null,"abstract":"<p>The continued spread of drug-resistant <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) necessitates thedevelopment of new chemotypes with novel modes of action. Here, wereport 5-carboxamide-substituted barbituric acid as a promising scaffoldfor developing new drugs against <em>Mtb</em>. Fenoxacrim,the initial hit compound identified through phenotypic screening,demonstrated potent activity against <em>Mtb</em>. It is activeagainst drug-susceptible and multidrug-resistant clinical <em>Mtb</em> isolates as well as against intracellular <em>Mtb</em> in infected THP-1 derived macrophages. Fenoxacrim demonstrates highselectivity (&gt;73-fold) for the pathogen over several tested mammaliancell lines. Other than <em>Mtb</em>, fenoxacrim exhibits strongbactericidal activity against several Gram-positive pathogens, including <em>methicillin-resistant</em><em>Staphylococcus aureus</em> (<em>MRSA</em>), with <em>in vitro</em> potencycomparable to, or exceeding several clinically used antibiotics. Medicinalchemistry optimization efforts yielded new fenoxacrim analogues withimproved <em>Mtb</em> specificity, enhanced potency, and reducedcytotoxicity. Mode-of-action studies suggest that fenoxacrim inhibitsundecaprenyl pyrophosphate synthase (UPPS) and dissipates the bacterialmembrane potential. Together, these findings highlight the potentialof 5-carboxamidebarbituric acid derivatives as a foundation for developingnew antibacterial agents with novel modes of action for the treatmentof tuberculosis and other drug-resistant bacterial infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3191–3203"},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943757","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}