Salud Rodríguez-Pallares, Tania Blanco-Martín, Emilio Lence, Pablo Aja-Macaya, Lucía Sánchez-Peña, Lucía González-Pinto, María Rodríguez-Mayo, Ana Fernández-González, Fátima Galán-Sánchez, Alejandro Beceiro, Concepción González-Bello, Germán Bou, Jorge Arca-Suárez
{"title":"<i>In vivo</i> emergence of resistance to ceftazidime/avibactam through modification of chromosomal AmpC β-lactamase in <i>Klebsiella aerogenes</i>.","authors":"Salud Rodríguez-Pallares, Tania Blanco-Martín, Emilio Lence, Pablo Aja-Macaya, Lucía Sánchez-Peña, Lucía González-Pinto, María Rodríguez-Mayo, Ana Fernández-González, Fátima Galán-Sánchez, Alejandro Beceiro, Concepción González-Bello, Germán Bou, Jorge Arca-Suárez","doi":"10.1128/aac.01307-24","DOIUrl":"10.1128/aac.01307-24","url":null,"abstract":"<p><p>We describe the <i>in vivo</i> emergence of resistance to ceftazidime/avibactam via modification of AmpC in a clinical <i>Klebsiella aerogenes</i> isolate during therapy with this combination. Paired ceftazidime/avibactam-susceptible/resistant isolates were obtained before and during ceftazidime/avibactam treatment. Whole genome sequencing revealed a differential mutation in AmpC (R148W) in the ceftazidime/avibactam-resistant isolate. Molecular cloning and structural studies confirmed the impact of this substitution, which affects the architecture of the H10 helix, on the evolved resistant phenotype.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0130724"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581296","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}
Hui Zhao, Yue Hu, Dan Nie, Na Li, Zhou Chen, Shan Zhou, Mingkai Li, Xiaoyan Xue
{"title":"A peptide targeting outer membrane protein A of <i>Acinetobacter baumannii</i> exhibits antibacterial activity by reducing bacterial pathogenicity.","authors":"Hui Zhao, Yue Hu, Dan Nie, Na Li, Zhou Chen, Shan Zhou, Mingkai Li, Xiaoyan Xue","doi":"10.1128/aac.00565-24","DOIUrl":"10.1128/aac.00565-24","url":null,"abstract":"<p><p>The World Health Organization has classified multidrug-resistant (MDR) <i>Acinetobacter baumannii</i> as a significant threat to human health, necessitating the urgent discovery of new antibacterial drugs to combat bacterial resistance. Outer membrane protein A of <i>A. baumannii</i> (AbOmpA) is an outer membrane-anchored β-barrel-shaped pore protein that plays a critical role in bacterial adhesion, invasion, and biofilm formation. Therefore, AbOmpA is considered a key virulence factor of <i>A. baumannii</i>. Herein, we screened three phage display peptide libraries targeting AbOmpA and identified several peptides. Among them, P92 (amino acid sequence: QMGFMTSPKHSV) exhibited the highest binding affinity with AbOmpA, with a KD value of 7.84 nM. <i>In vitro</i> studies demonstrated that although P92 did not directly inhibit bacterial growth, it significantly reduced the invasion and adhesion capabilities of multiple clinical isolates of MDR <i>A. baumannii</i> and concentration-dependently inhibited biofilm formation by acting on OmpA. Furthermore, the polymerase chain reaction results confirmed a significant positive correlation between the antibacterial effect of P92 and OmpA expression levels. Encouragingly, P92 also displayed remarkable therapeutic efficacy against <i>A. baumannii</i> infection in various models, including an <i>in vitro</i> cell infection model, a mouse skin infection model, and a mouse sepsis model. These results highlight P92 as a novel and highly effective antimicrobial molecule specifically targeting the virulence factor AbOmpA.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0056524"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581299","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":"Reply to Boyd et al., \"Evidence that remdesivir treatment reduces viral titers in patients with COVID-19\".","authors":"Isa Faghihi, Victoria C Yan","doi":"10.1128/aac.01363-24","DOIUrl":"10.1128/aac.01363-24","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0136324"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602856","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":"Multigeographic clinical assessment of a molecular diagnostic assay for detection of key codons to predict decreased susceptibility or resistance to cephalosporins in <i>Neisseria gonorrhoeae</i>.","authors":"Liqin Wang, Yamei Li, Leshan Xiu, Lihua Hu, Jia Huang, Gang Yong, Youwei Wang, Wenling Cao, Yang Yang, Feng Wang, Weiming Gu, Junping Peng","doi":"10.1128/aac.01165-24","DOIUrl":"10.1128/aac.01165-24","url":null,"abstract":"<p><p>Cephalosporin resistance in <i>Neisseria gonorrhoeae</i> has severely compromised the efficacy of World Health Organization (WHO)-recommended therapies. This study aimed to methodologically evaluate the optimized Six-Codon<sup>Plus</sup> assay, and additionally conducted a multicenter evaluation to assess its clinical application, especially for predicting antimicrobial resistance (AMR). For methodological evaluation, 397 sequence-known <i>N. gonorrhoeae</i> isolates were evaluated for specificity, 17 nongonococcal isolates were assessed for cross-reactivity, 159 uncultured urogenital swabs and urine samples were evaluated for sensitivity at the clinical level. For multicenter evaluation, 773 isolates with confirmed phenotypic data and 718 clinical urogenital swabs collected from four geographical cities were, respectively, utilized for the evaluation of AMR-prediction strategies and the clinical application of the assay. The assay accurately identified specific single-nucleotide polymorphisms in resistance-associated genes, the detection limits dropped to 10 copies/reaction for individual targets. The specificity reached 100% and no cross-reactivity occurred with double-target confirmation. The assay could be directly applied to clinical samples containing over 20 copies/reaction. Multicenter evaluation formulated two optimal strategies for decreased susceptibility prediction in specific scenarios, and one tactic for prediction of resistance and identification of FC428-like strains. High sensitivity of 86.84% (95% CI, 71.11-95.05) and specificity of 99.59% (95% CI, 98.71-99.89) for resistance prediction were demonstrated for ceftriaxone (CRO). Regarding <i>N. gonorrhoeae</i> identification among multicenter swabs, specificity reached 97.53% (95% CI, 95.49-98.69), and sensitivity reached 93.77% (95% CI, 90.04-96.22). The Six-Codon<sup>Plus</sup> assay exhibited excellent detection performance and formulated optimal AMR-related prediction strategy with regional adaptability, providing critical information for population screening and clinical treatment.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0116524"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11620283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520818","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}
Alexander J Sundermann, Rossana Rosa, Patrick N A Harris, Evan Snitkin, Waleed Javaid, Nicholas M Moore, Mary K Hayden, Krisandra Allen, Kyle Rodino, Sharon J Peacock, Lilian M Abbo, Lee H Harrison
{"title":"Pathogen genomics in healthcare: overcoming barriers to proactive surveillance.","authors":"Alexander J Sundermann, Rossana Rosa, Patrick N A Harris, Evan Snitkin, Waleed Javaid, Nicholas M Moore, Mary K Hayden, Krisandra Allen, Kyle Rodino, Sharon J Peacock, Lilian M Abbo, Lee H Harrison","doi":"10.1128/aac.01479-24","DOIUrl":"https://doi.org/10.1128/aac.01479-24","url":null,"abstract":"<p><p>Pathogen genomic surveillance in healthcare has the potential to enhance patient safety by detecting outbreaks earlier, thereby reducing morbidity and mortality. Despite benefits, there are barriers to adoption, including cost, expertise, and lack of standardized methodologies and incentives. This commentary advocates for 1) investment from healthcare payors, public health, and regulatory bodies and 2) additional research on genomic surveillance for improving patient outcomes and reducing infections. Effective implementation will require strategic investment and cross-sector collaboration.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0147924"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783670","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}
Michael R Jacobs, Caryn E Good, Ayman M Abdelhamed, Andrew R Mack, Christopher R Bethel, Steven H Marshall, Andrea M Hujer, Kristine M Hujer, Robin Patel, David van Duin, Vance G Fowler, Daniel D Rhoads, David A Six, Greg Moeck, Tsuyoshi Uehara, Krisztina M Papp-Wallace, Robert A Bonomo
{"title":"ARGONAUT-IV: susceptibility of carbapenemase-producing <i>Klebsiella pneumoniae</i> to the oral bicyclic boronate β-lactamase inhibitor ledaborbactam combined with ceftibuten.","authors":"Michael R Jacobs, Caryn E Good, Ayman M Abdelhamed, Andrew R Mack, Christopher R Bethel, Steven H Marshall, Andrea M Hujer, Kristine M Hujer, Robin Patel, David van Duin, Vance G Fowler, Daniel D Rhoads, David A Six, Greg Moeck, Tsuyoshi Uehara, Krisztina M Papp-Wallace, Robert A Bonomo","doi":"10.1128/aac.01127-24","DOIUrl":"10.1128/aac.01127-24","url":null,"abstract":"<p><p>Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant <i>Klebsiella pneumoniae</i> isolates, predominantly <i>K. pneumoniae</i> carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0112724"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543320","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}
ThanhPhuong M Le, Taryn A Eubank, Ann M McKelvey, Xinyun Cao, Julian G Hurdle, Kevin W Garey
{"title":"Fidaxomicin resistance in <i>Clostridioides difficile</i>: a systematic review and predictive modeling with RNA polymerase binding sites.","authors":"ThanhPhuong M Le, Taryn A Eubank, Ann M McKelvey, Xinyun Cao, Julian G Hurdle, Kevin W Garey","doi":"10.1128/aac.01206-24","DOIUrl":"10.1128/aac.01206-24","url":null,"abstract":"<p><p>Fidaxomicin (FDX), an RNA polymerase (RNAP) inhibitor antibiotic, is a guideline-recommended therapy for <i>Clostridioides difficile</i> infection. Mutations associated with reduced FDX minimum inhibitory concentrations (MICs) have been identified. However, the molecular characterization of these mutations on FDX binding and the development of FDX resistance have not been studied. The purpose of this systematic review was to identify FDX resistance in <i>C. difficile</i> isolates and determine whether single nucleotide polymorphisms associated with increased FDX MIC aligned with the RNAP binding pocket interacting residues. A systematic literature search was done in PubMed (1991-2023) with identified articles and their bibliographies searched for papers that included <i>C. difficile</i> genetic mutations and increased FDX MIC. Visualization of FDX-RNAP interactions was performed on Schrödinger Maestro using the publicly available <i>C. difficile</i> RNAP with fidaxomicin sequence (code 7L7B) on the Protein Data Bank. Seven articles were identified after applying inclusion and exclusion criteria. The most common mutation in clinical and laboratory isolates was at position V1143 of the β subunit, which accounted for approximately 50% of the identified mutations. Most other mutations occurred within the β' subunit of RNAP. Approximately one-third of the identified mutation aligned directly with FDX interacting residues with <i>C. difficile</i> RNAP (7/20) with most of the remainder occurring within 5 Å of the binding residues. <i>C. difficile</i> strains with elevated FDX MIC align closely with the known RNAP binding residues. These data demonstrate the potential to identify genomic methods to identify emerging FDX resistance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0120624"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581241","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}
Heidi Segers, Jaime G Deville, William J Muller, Angela Manzanares, Amit Desai, Michael Neely, Victoria Bordon, Benjamin Hanisch, Alvaro Lassaletta, Brian T Fisher, Julie Autmizguine, Andreas H Groll, Shamim Sinnar, Rodney Croos-Dabrera, Marc Engelhardt, Mark Jones, Laura L Kovanda, Antonio C Arrieta
{"title":"Safety, outcomes, and pharmacokinetics of isavuconazole as a treatment for invasive fungal diseases in pediatric patients: a non-comparative phase 2 trial.","authors":"Heidi Segers, Jaime G Deville, William J Muller, Angela Manzanares, Amit Desai, Michael Neely, Victoria Bordon, Benjamin Hanisch, Alvaro Lassaletta, Brian T Fisher, Julie Autmizguine, Andreas H Groll, Shamim Sinnar, Rodney Croos-Dabrera, Marc Engelhardt, Mark Jones, Laura L Kovanda, Antonio C Arrieta","doi":"10.1128/aac.00484-24","DOIUrl":"10.1128/aac.00484-24","url":null,"abstract":"<p><p>Invasive aspergillosis (IA) and mucormycosis (IM) cause significant morbidity and mortality in immunocompromised and/or hospitalized patients. Isavuconazonium sulfate, a prodrug of the antifungal triazole isavuconazole, has been approved for treatment of IA and IM in adults; and was recently approved in children. This study describes the outcomes, safety, and pharmacokinetics of isavuconazole for the treatment of proven, probable, or possible IA or IM in children. In this phase 2, open-label, non-comparative study, patients aged 1 to <18 years with at least possible invasive mold disease were enrolled across 10 centers in the US, Spain, and Belgium from 2019 to 2022. Patients received 10 mg/kg isavuconazonium sulfate daily (maximum 372 mg; equivalent to 5.4 mg/kg or 200 mg isavuconazole) for up to 84 (IA) or 180 days (IM). Outcomes included rates of all-cause case fatality, overall response, treatment-emergent adverse events (TEAEs), and pharmacokinetics. Of 31 patients enrolled, 61.3% were 1-<12 years old; 58.1% had underlying hematologic malignancies. The successful overall response rate at the end of treatment was 54.8%. Day 42 all-cause case fatality was 6.5%; 93.5% experienced TEAEs, and two patients discontinued treatment due to drug-related TEAEs. Dosing at 10 mg/kg (maximum dose: 372 mg) met the pre-defined exposure threshold of above the 25th percentile for the area under the concentration-time curve (≥60 mg·h/L). Simulated doses of 15 mg/kg improved drug exposures in patients aged 1-<3 years. Isavuconazole was well tolerated in children, with exposure consistent with adult studies. Successful response was documented in 54.8% of patients.CLINICAL TRIALSThis study is registered at ClinicalTrials.gov as NCT03816176.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0048424"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11642194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613882","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}
Edwin Pierre-Louis, Julia Kelley, Dhruviben Patel, Christina Carlson, Eldin Talundzic, David Jacobson, Joel Leonard Nicholas Barratt
{"title":"Geo-classification of drug-resistant travel-associated <i>Plasmodium falciparum</i> using <i>Pfs47</i> and <i>Pfcpmp</i> gene sequences (USA, 2018-2021).","authors":"Edwin Pierre-Louis, Julia Kelley, Dhruviben Patel, Christina Carlson, Eldin Talundzic, David Jacobson, Joel Leonard Nicholas Barratt","doi":"10.1128/aac.01203-24","DOIUrl":"10.1128/aac.01203-24","url":null,"abstract":"<p><p>Travel-related malaria is regularly encountered in the United States, and the U.S. Centers for Disease Control and Prevention (CDC) characterizes <i>Plasmodium falciparum</i> drug-resistance genotypes routinely for travel-related cases. An important aspect of antimalarial drug resistance is understanding its geographic distribution. However, specimens submitted to CDC laboratories may have missing, incomplete, or inaccurate travel data. To complement genotyping for drug-resistance markers <i>Pfcrt</i>, <i>Pfmdr1</i>, <i>Pfk13</i>, <i>Pfdhps</i>, <i>Pfdhfr</i>, and <i>PfcytB</i> at CDC, amplicons of <i>Pfs47</i> and <i>Pfcpmp</i> are also sequenced as markers of geographic origin. Here, a bi-allele likelihood (BALK) classifier was trained using <i>Pfs47</i> and <i>Pfcpmp</i> sequences from published <i>P. falciparum</i> genomes of known geographic origin to classify clinical genotypes to a continent. Among <i>P. falciparum</i>-positive blood samples received at CDC for drug-resistance genotyping from 2018 to 2021 (<i>n</i> = 380), 240 included a travel history with the submission materials, though 6 were excluded due to low sequence quality. Classifications obtained for the remaining 234 were compared to their travel histories. Classification results were over 96% congruent with reported travel for clinical samples, and with collection sites for field isolates. Among travel-related samples, only two incongruent results occurred; a specimen submitted citing Costa Rican travel classified to Africa, and a specimen with travel referencing Sierra Leone classified to Asia. Subsequently, the classifier was applied to specimens with unreported travel histories (<i>n</i> = 140; 5 were excluded due to low sequence quality). For the remaining 135 samples, geographic classification data were paired with results generated using CDC's Malaria Resistance Surveillance (MaRS) protocol, which detects single-nucleotide polymorphisms in and generates haplotypes for <i>Pfcrt</i>, <i>Pfmdr1</i>, <i>Pfk13</i>, <i>Pfdhps</i>, <i>Pfdhfr</i>, and <i>PfcytB</i>. Given the importance of understanding the geographic distribution of antimalarial drug resistance, this work will complement domestic surveillance efforts by expanding knowledge on the geographic origin of drug-resistant <i>P. falciparum</i> entering the USA.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0120324"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613864","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}
Luis Alberto Vega, Misú Sanson-Iglesias, Piyali Mukherjee, Kyle D Buchan, Gretchen Morrison, Anne E Hohlt, Anthony R Flores
{"title":"LiaR-dependent gene expression contributes to antimicrobial responses in group A <i>Streptococcus</i>.","authors":"Luis Alberto Vega, Misú Sanson-Iglesias, Piyali Mukherjee, Kyle D Buchan, Gretchen Morrison, Anne E Hohlt, Anthony R Flores","doi":"10.1128/aac.00496-24","DOIUrl":"10.1128/aac.00496-24","url":null,"abstract":"<p><p>The ability to sense and respond to host defenses is essential for pathogen survival. Some mechanisms involve two-component systems (TCSs) that respond to host molecules, such as antimicrobial peptides (AMPs), and activate specific gene regulatory pathways to aid in survival. Alongside TCSs, bacteria coordinate cell division proteins, chaperones, cell wall sortases, and secretory translocons at discrete locations within the cytoplasmic membrane, referred to as functional membrane microdomains (FMMs). In group A <i>Streptococcus</i> (GAS), the FMM or \"ExPortal\" coordinates protein secretion, cell wall synthesis, and sensing of AMP-mediated cell envelope stress <i>via</i> the LiaFSR three-component system. Previously, we showed that GAS exposure to a subset of AMPs (α-defensins) activates the LiaFSR system by disrupting LiaF and LiaS co-localization in the ExPortal, leading to increased LiaR phosphorylation, expression of the transcriptional regulator SpxA2, and altered GAS virulence gene expression. The mechanisms by which LiaFSR integrates cell envelope stress with responses to AMP activity and virulence are not fully elucidated. Here, we show the LiaFSR regulon is comprised of genes encoding SpxA2 and three membrane-associated proteins: a PspC domain-containing protein (PCP), the lipoteichoic acid-modifying protein LafB, and the membrane protein insertase YidC2. Our data support that phosphorylated LiaR induces transcription of these genes <i>via</i> a conserved operator, whose disruption attenuates GAS virulence and increases susceptibility to AMPs in a manner primarily dependent on differential expression of SpxA2. Our work expands our understanding of the LiaFSR regulatory network in GAS and identifies targets for further investigation of mechanisms of cell envelope stress tolerance contributing to GAS pathogenesis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0049624"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613868","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}