Maria Cidinaria Silva Alves*, Mireli Santana Rego, Ruana Carolina Cabral da Silva, Rousilândia de Araújo Silva, Igor Eduardo Silva Arruda, Sérgio de Sá Leitão Paiva-Júnior and Valdir de Queiroz Balbino*,
{"title":"","authors":"Maria Cidinaria Silva Alves*, Mireli Santana Rego, Ruana Carolina Cabral da Silva, Rousilândia de Araújo Silva, Igor Eduardo Silva Arruda, Sérgio de Sá Leitão Paiva-Júnior and Valdir de Queiroz Balbino*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00250","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595021","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":"Halogenated Sulfono-γ-AApeptides Modified Cationic AMPs Have Enhanced Stability and Therapeutic Potential against Clinically Important MDR Infections.","authors":"Xiaomin Guo, Yingying An, Tiantian Yan, Yue Jia, Ruoyan Jiao, Xinyu Cai, Weili Yang, Guangjun Bao, Wangsheng Sun, Wenle Yang, Ningning Lu, Junqiu Xie","doi":"10.1021/acsinfecdis.5c00312","DOIUrl":"10.1021/acsinfecdis.5c00312","url":null,"abstract":"<p><p>Antimicrobial peptides have garnered increasing attention and are anticipated to address the growing crisis of antibiotic resistance. However, their inadequate proteolytic stability poses significant challenges for clinical development. In this study, we present a highly effective strategy to overcome the limitations by introducing multiple halogenated sulfono-γ-AApeptides into cationic AMP Feleucin-K3. Surprisingly, K162 and K174, which feature sulfono-γ-AApeptide modifications containing iodinated or trifluoromethyl groups, exhibit powerful antibacterial and antibiofilm activities, while having significantly improved stability. Furthermore, they exhibited low resistance tendencies and were less susceptible to cross-resistance in comparison to antibiotics. Additionally, the two analogs exhibited superior safety and therapeutic potential compared to polymyxin B against pneumonia induced by multidrug-resistant <i>P. aeruginosa</i>. For skin- and catheter-biofilm-related infections caused by MRSA, K162, and K174 displayed comparable therapeutic effects compared to vancomycin. In conclusion, K162 and K174 are considered novel antimicrobial alternatives to combat multidrug-resistant bacterial infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"2018-2036"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281667","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}
ACS Infectious DiseasesPub Date : 2025-07-11Epub Date: 2025-06-09DOI: 10.1021/acsinfecdis.5c00209
Alexanndra M Behm, Huili Yao, Emmanuel C Eze, Suliat A Alli, Simon D P Baugh, Ebenezer Ametsetor, Kendall M Powell, Kevin P Battaile, Steve Seibold, Scott Lovell, Richard A Bunce, Allen B Reitz, Mario Rivera
{"title":"Inhibitors of the Bacterioferritin Ferredoxin Complex Dysregulate Iron Homeostasis and Kill <i>Acinetobacter baumannii</i> and Biofilm-Embedded <i>Pseudomonas aeruginosa</i> Cells.","authors":"Alexanndra M Behm, Huili Yao, Emmanuel C Eze, Suliat A Alli, Simon D P Baugh, Ebenezer Ametsetor, Kendall M Powell, Kevin P Battaile, Steve Seibold, Scott Lovell, Richard A Bunce, Allen B Reitz, Mario Rivera","doi":"10.1021/acsinfecdis.5c00209","DOIUrl":"10.1021/acsinfecdis.5c00209","url":null,"abstract":"<p><p>In <i>Pseudomonas aeruginosa</i>, the iron storage protein bacterioferritin (Bfr) contributes to buffering cytosolic free iron concentrations by oxidizing Fe<sup>2+</sup> and storing the resultant Fe<sup>3+</sup> in its internal cavity, and by forming a complex with a cognate ferredoxin (Bfd) to reduce the stored Fe<sup>3+</sup> and mobilize Fe<sup>2+</sup> to the cytosol. Small molecule derivatives of 4-aminoisoindoline-1,3-dione designed to bind <i>P. aeruginosa</i> Bfr (Pa Bfr) at the Bfd binding site accumulate in the <i>P. aeruginosa</i> cell, block the Pa Bfr-Bfd complex, inhibit iron mobilization from Pa Bfr, elicit an iron starvation response, are bacteriostatic to planktonic cells, and are bactericidal to biofilm-entrenched cells. A structural alignment of Pa Bfr and <i>Acinetobacter baumannii</i> Bfr (Ab Bfr) showed strong conservation of the Bfd binding site on Ab Bfr. Accordingly, the small molecule inhibitors of the Pa Bfr-Bfd complex accumulate in the <i>A. baumannii</i> cells, elicit an iron starvation response, are bactericidal to planktonic cells, and exhibit synergy with existing antibiotics. These findings indicate that the inhibition of iron mobilization from Bfr may be an antimicrobial strategy applicable to other Gram-negative pathogens.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1983-1993"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256629","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}
ACS Infectious DiseasesPub Date : 2025-07-11Epub Date: 2025-06-17DOI: 10.1021/acsinfecdis.5c00150
Nicole A Malofsky, Swayashreyee B Dhungel, Megan E Pask, Frederick R Haselton
{"title":"Single-Sample Melt-Based Screening for Rifampicin Susceptibility in the Emerging Mutation Hotspot at <i>rpoB</i> Codon 491.","authors":"Nicole A Malofsky, Swayashreyee B Dhungel, Megan E Pask, Frederick R Haselton","doi":"10.1021/acsinfecdis.5c00150","DOIUrl":"10.1021/acsinfecdis.5c00150","url":null,"abstract":"<p><p>Based on sequencing data, mutations at <i>rpoB</i> codon 491 of<i>Mycobacterium tuberculosis</i>are associated with rifampicin resistance, but current commercial and WHO-endorsed genotypic tests fail to detect them. As a result, resistant infections go untreated, driving transmission and multidrug resistance. A real-time PCR assay by André et al. specifically screens for I491F but omits other codon 491 mutations. To address this gap, a single-sample screening method using asymmetric PCR followed by melt analysis was developed for the three sequence-identified variants, I491F/N/M. Each sample contained a melt probe matching the susceptible sequence, which, after asymmetric PCR spanning codon 491, hybridized with the excess strand to form a duplex. The duplex's melt temperature (<i>T</i><sub>m</sub>) was then measured. To enable single-sample classification, each reaction also included double-stranded L-DNA identical to the probe and wild-type PCR product duplex. Susceptibility was determined by the within-sample <i>T</i><sub>m</sub> difference between the probe-product and L-DNA duplexes. The approach was evaluated and compared to the André assay across two calibrated PCR instruments using synthetic <i>rpoB</i> wild-type and variant sequences. As expected, the André assay distinguished wild-type from I491F samples but misclassified I491N and I491M samples based on multisample <i>T</i><sub>m</sub> comparison. In contrast, our single-sample classification strategy used within-sample <i>T</i><sub>m</sub> differences, classifying samples as rifampicin-susceptible when the within-sample <i>T</i><sub>m</sub> difference was less than 0.83 °C. With this approach, the method achieved 100% sensitivity and 100% specificity across both PCR instruments. Although demonstrated for <i>rpoB</i> codon 491, this assay design is readily adaptable to any other sequence-identified, clinically significant mutation hotspot.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1934-1943"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315503","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}
ACS Infectious DiseasesPub Date : 2025-07-11Epub Date: 2025-06-05DOI: 10.1021/acsinfecdis.4c01062
Irene Lepori, Kiserian Jackson, Zichen Liu, Mahendra D Chordia, Mitchell Wong, Sylvia L Rivera, Marta Roncetti, Laura Poliseno, Joel S Freundlich, Marcos M Pires, M Sloan Siegrist
{"title":"The Mycomembrane Differentially and Heterogeneously Restricts Antibiotic Permeation.","authors":"Irene Lepori, Kiserian Jackson, Zichen Liu, Mahendra D Chordia, Mitchell Wong, Sylvia L Rivera, Marta Roncetti, Laura Poliseno, Joel S Freundlich, Marcos M Pires, M Sloan Siegrist","doi":"10.1021/acsinfecdis.4c01062","DOIUrl":"10.1021/acsinfecdis.4c01062","url":null,"abstract":"<p><p>The recalcitrance of <i>Mycobacterium tuberculosis</i> to antibiotic treatment has been broadly attributed to the impermeability of the organism's outer mycomembrane. However, the studies that support this inference have been indirect or reliant on bulk population measurements. We previously developed the Peptidoglycan Accessibility Click-Mediated AssessmeNt (PAC-MAN) method to covalently trap azide-modified small molecules in the peptidoglycan cell wall of live mycobacteria after they have traversed the mycomembrane. Using PAC-MAN, we now show that the mycomembrane differentially restricts access to fluorophores and antibiotic derivatives. Mycomembranes of both <i>M. tuberculosis</i> and the model organism <i>Mycobacterium smegmatis</i> discriminate between divergent classes of antibiotics as well as between antibiotics within a single family, the fluoroquinolones. By analyzing subpopulations of <i>M. tuberculosis</i> and <i>M. smegmatis</i>, we also found that some fluorophores and vancomycin are heterogeneously restricted by the mycomembrane. Our data indicate that the mycomembrane is a molecule- and cell-specific barrier to antibiotic permeation.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1893-1906"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232622","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}
ACS Infectious DiseasesPub Date : 2025-07-11Epub Date: 2025-06-12DOI: 10.1021/acsinfecdis.5c00179
Addison M Duda, Helena R Ma, César A Villalobos, Sophia A Kuhn, Sarah S Angle, Katherine He, Abigail C Jackson, Christine M Suh, Elena A Puccio, Deverick J Anderson, Vance G Fowler, Lingchong You, Katherine J Franz
{"title":"An Engineered Prodrug Selectively Suppresses β-Lactam-Resistant Bacteria in a Mixed Microbial Setting.","authors":"Addison M Duda, Helena R Ma, César A Villalobos, Sophia A Kuhn, Sarah S Angle, Katherine He, Abigail C Jackson, Christine M Suh, Elena A Puccio, Deverick J Anderson, Vance G Fowler, Lingchong You, Katherine J Franz","doi":"10.1021/acsinfecdis.5c00179","DOIUrl":"10.1021/acsinfecdis.5c00179","url":null,"abstract":"<p><p>The rise of β-lactam resistance necessitates new strategies to combat bacterial infections. We purposefully engineered the β-lactam prodrug AcephPT to exploit β-lactamase activity to selectively suppress resistant bacteria producing extended-spectrum-β-lactamases (ESBLs). Selective targeting of resistant bacteria requires avoiding interaction with penicillin-binding proteins, the conventional targets of β-lactam antibiotics, while maintaining recognition by ESBLs to activate AcephPT only in resistant cells. We show that AcephPT selectively suppresses Gram-negative ESBL-producing bacteria in clonal populations and in mixed microbial cultures, with effective selectivity for both lab strains and clinical isolates expressing ESBLs. Time-course NMR experiments confirm the hydrolytic activation of AcephPT exclusively by ESBL-producing bacteria. In mixed microbial cultures, AcephPT suppresses proliferation of an ESBL-producing strain while sustaining growth of β-lactamase-nonproducing bacteria, highlighting its potential to combat β-lactam resistance while promoting antimicrobial stewardship.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1956-1967"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273651","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}
Tanja Karpstein, Apollonia Kalamatianou, Sarah Keller, Philipp Späne, Cécile Häberli, Alex Odermatt, Olivier Blacque, Kevin Cariou*, Gilles Gasser* and Jennifer Keiser*,
{"title":"","authors":"Tanja Karpstein, Apollonia Kalamatianou, Sarah Keller, Philipp Späne, Cécile Häberli, Alex Odermatt, Olivier Blacque, Kevin Cariou*, Gilles Gasser* and Jennifer Keiser*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595027","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}