mBio最新文献

{"title":"Cell envelope polysaccharide modifications alter the surface properties and interactions of <i>Mycobacterium abscessus</i> with innate immune cells in a morphotype-dependent manner.","authors":"Elena Lian, Juan M Belardinelli, Kavita De, Arun Prasad Pandurangan, Shiva K Angala, Zuzana Palčeková, Anna E Grzegorzewicz, Josephine M Bryant, Tom L Blundell, Julian Parkhill, R Andres Floto, William H Wheat, Mary Jackson","doi":"10.1128/mbio.00322-25","DOIUrl":"10.1128/mbio.00322-25","url":null,"abstract":"<p><p><i>Mycobacterium abscessus</i> is one of the leading causes of pulmonary infections caused by non-tuberculous mycobacteria. The ability of <i>M. abscessus</i> to establish a chronic infection in the lung relies on a series of adaptive mutations impacting, in part, global regulators and cell envelope biosynthetic enzymes. One of the genes under strong evolutionary pressure during host adaptation is <i>ubiA</i>, which participates in the elaboration of the arabinan domains of two major cell envelope polysaccharides: arabinogalactan (AG) and lipoarabinomannan (LAM). We here show that patient-derived UbiA mutations not only cause alterations in the AG, LAM, and mycolic acid contents of <i>M. abscessus</i> but also tend to render the bacterium more prone to forming biofilms while evading uptake by innate immune cells and enhancing their pro-inflammatory properties. The fact that the effects of UbiA mutations on the physiology and pathogenicity of <i>M. abscessus</i> were impacted by the rough or smooth morphotype of the strain suggests that the timing of their selection relative to morphotype switching may be key to their ability to promote chronic persistence in the host.IMPORTANCEMultidrug-resistant pulmonary infections caused by <i>Mycobacterium abscessus</i> and subspecies are increasing in the U.S.A. and globally. Little is known of the mechanisms of pathogenicity of these microorganisms. We have identified single-nucleotide polymorphisms (SNPs) in a gene involved in the biosynthesis of two major cell envelope polysaccharides, arabinogalactan and lipoarabinomannan, in lung-adapted isolates from 13 patients. Introduction of these individual SNPs in a reference <i>M. abscessus</i> strain allowed us to study their impact on the physiology of the bacterium and its interactions with immune cells. The significance of our work is in identifying some of the mechanisms used by <i>M. abscessus</i> to colonize and persist in the human lung, which will facilitate the early detection of potentially more virulent clinical isolates and lead to new therapeutic strategies. Our findings may further have broader biomedical impacts, as the <i>ubiA</i> gene is conserved in other tuberculous and non-tuberculous mycobacterial pathogens.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0032225"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metagenomic and transcriptomic investigation of pediatric acute liver failure cases reveals a common pathway predominated by monocytes.","authors":"Ruben H de Kleine, Ellen C Carbo, Willem S Lexmond, Xuewei W Zhou, Alicia de Kroon, Hailiang Mei, Sander T H Bontemps, Rick Hennevelt, Lilli Gard, Igor A Sidorov, Stefan A Boers, Marius C van den Heuvel, Emilie P Buddingh, Aloys C M Kroes, Vincent E de Meijer, Elisabeth H Schölvinck, Karin J von Eije, Simon P Jochems, Jutte J C de Vries","doi":"10.1128/mbio.03913-24","DOIUrl":"10.1128/mbio.03913-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;In 2022, a cluster of severe childhood hepatitis was detected primarily in Europe and North America, leading to a global alert by the World Health Organization. An association with adeno-associated virus 2 (AAV2) in conjunction with human adenoviruses was found. Five percent of the cases progressed to acute liver failure, necessitating transplantation. The mechanism of disease that accounts for fulminant liver failure in these patients remains incompletely described. An upsurge was observed of in the five total cases of acute liver failure that presented to the Dutch national referral center for pediatric liver transplantation in the spring of 2022. An in-depth molecular analysis of the mechanism of pediatric acute liver failure was performed using targeted transcriptomics and metagenomics to identify any virus present in the cases, immune profile haplotypes, and differentially expressed gene groups. Explanted liver tissue and plasma samples (&lt;i&gt;n&lt;/i&gt; = 15) were subjected to viral metagenomic and human transcriptomic profiling, targeting &gt;600 inflammatory genes. Liver transcriptomic signatures of transplanted cases were compared with those of pediatric controls from a liver biobank (&lt;i&gt;n&lt;/i&gt; = 6). AAV2, adenoviruses, and herpesviruses were detected in liver explant tissue and plasma samples of the cases. Epstein-Barr virus and varicella zoster virus infection with pathognomonic clinical symptomatology preceded liver failure in two respective cases. AAV2 was detected in one-third of control livers. Excessive activation of monocyte pathways was detected in liver explants from cases compared with controls. Remarkably, this signature was comparable for AAV2, adenoviruses, and/or herpesviruses-positive transplant cases. Our multi-omic findings suggest a common transcriptomic profile, with an upregulation of monocyte pathways in the presented transplanted cases, which had similar severe clinical outcomes. In the cohort presented, AAV2 was not exclusively associated with acute liver failure, suggesting that other processes may have contributed to a uniform cascade of irreversible pathology.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Since the appearance of the cluster of pediatric hepatitis of unknown origin in 2022, several groups have reported an association of adenoviruses and AAV2 in a high number of cases in contrast to controls. The adenoviruses detected were heterogeneous in both species-adenovirus C and F-and sequences. The mechanisms of disease that accounts for fulminant liver failure, occurring in 5% of pediatric hepatitis cases, remain incompletely described. The current study adds to previous data by including pediatric acute liver failure cases during the upsurge, enabling the analyses of inflammation expression profiles in cases with different viruses in relation to pediatric controls. This led to the discovery of transcriptome upregulation of monocyte pathways in liver explants from the cases. This inflammatory transcriptomic signature was","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0391324"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency in peptidoglycan recycling promotes β-lactam sensitivity in <i>Caulobacter crescentus</i>.","authors":"Malvika Modi, Deepika Chauhan, Michael C Gilmore, Felipe Cava, Richa Priyadarshini","doi":"10.1128/mbio.02975-24","DOIUrl":"10.1128/mbio.02975-24","url":null,"abstract":"<p><p>Peptidoglycan (PG)-modifying enzymes play a crucial role in cell wall remodeling, essential for growth and division. Cell wall degradation products are transported to the cytoplasm and recycled back in most gram-negative bacteria, and PG recycling is also linked to β-lactam resistance in many bacteria. <i>Caulobacter crescentus</i> is intrinsically resistant to β-lactams. Recently, it was shown that a soluble lytic transglycosylase, SdpA, is essential for β-lactam resistance. However, the precise role of SdpA in β-lactam resistance is unknown. This study investigated the PG recycling pathway and its role in antibiotic resistance in <i>C. crescentus</i>. Anhydromuropeptides generated by the action of lytic transglycosylases (LTs) are transported to the cytoplasm by the permease AmpG. <i>C. crescentus</i> encodes an <i>ampG</i> homolog, and deletion mutants of <i>sdpA</i> and <i>ampG</i> are sensitive to β-lactams. The <i>ampG</i> deletion mutant displays a significant accumulation of anhydromuropeptides in the periplasm of <i>C. crescentus,</i> demonstrating its essential role in PG recycling. While single knockout mutants of <i>sdpA</i> and <i>ampG</i> exhibit no growth defects, double-deletion mutants (∆<i>sdpA</i>∆<i>ampG</i>) exhibit severe growth and morphological defects. These double mutants also show enhanced sensitivity to β-lactams. Analysis of soluble muropeptides in wild-type (WT), ∆<i>sdpA</i>, and ∆<i>ampG</i> mutants revealed reduced levels of PG precursors (UDP-GlcNAc, UDP-MurNAc, and UDP-MurNAc-P5), suggesting that PG recycling products contribute toward <i>de novo</i> PG biosynthesis. Furthermore, supplementing the growth media with GlcNAc sugar enhanced the fitness of ∆<i>sdpA</i> and ∆<i>ampG</i> mutants under β-lactam stress. In conclusion, our study indicates that defects in PG recycling compromise cell wall biogenesis, leading to antibiotic sensitivity in <i>C. crescentus</i>.<b>IMPORTANCE</b>β-lactam antibiotics target the peptidoglycan cell wall biosynthetic pathway in bacteria. In response to antibiotic pressures, bacteria have developed various resistance mechanisms. In many gram-negative species, cell wall degradation products are transported into the cytoplasm and induce the expression of β-lactamase enzymes. In this study, we investigated the cell wall recycling pathway and its role in antibiotic resistance in <i>Caulobacter crescentus</i>. Based on our data and prior studies, we propose that cell wall degradation products are utilized for the synthesis of peptidoglycan precursors in the cytoplasm. A deficiency in cell wall recycling leads to cell wall defects and increased antibiotic sensitivity in <i>C. crescentus</i>. These findings are crucial for understanding antibiotic resistance mechanisms in bacteria.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0297524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Penton blooming, a conserved mechanism of genome delivery used by disparate microviruses.","authors":"Pavol Bardy, Conor I W MacDonald, Paul C Kirchberger, Huw T Jenkins, Tibor Botka, Lewis Byrom, Nawshin T B Alim, Daouda A K Traore, Hannah C Koenig, Tristan R Nicholas, Maria Chechik, Samuel J Hart, Johan P Turkenburg, James N Blaza, J Thomas Beatty, Paul C M Fogg, Alfred A Antson","doi":"10.1128/mbio.03713-24","DOIUrl":"10.1128/mbio.03713-24","url":null,"abstract":"<p><p>Microviruses are single-stranded DNA viruses infecting bacteria, characterized by T = 1 shells made of single jelly-roll capsid proteins. To understand how microviruses infect their host cells, we have isolated and studied an unusually large microvirus, Ebor. Ebor belongs to the proposed \"Tainavirinae\" subfamily of <i>Microviridae</i> and infects the model Alphaproteobacterium <i>Rhodobacter capsulatus</i>. Using cryogenic electron microscopy, we show that the enlarged capsid of Ebor is the result of an extended C-terminus of the major capsid protein. The extra packaging space accommodates genes encoding a lytic enzyme and putative methylase, both absent in microviruses with shorter genomes. The capsid is decorated with protrusions at its 3-fold axes, which we show to recognize lipopolysaccharides on the host surface. Cryogenic electron tomography shows that during infection, Ebor attaches to the host cell via five such protrusions. This attachment brings a single pentameric capsomer into close contact with the cell membrane, creating a special vertex through which the genome is ejected. Both subtomogram averaging and single particle analysis identified two intermediates of capsid opening, showing that the interacting penton opens from its center via the separation of individual capsomer subunits. Structural comparison with the model <i>Bullavirinae</i> phage phiX174 suggests that this genome delivery mechanism may be widely present across <i>Microviridae</i>.</p><p><strong>Importance: </strong>Tailless <i>Microviridae</i> bacteriophages are major components of the global virosphere. Notably, microviruses are prominent members of the mammalian gut virome, and certain compositions have been linked to serious health disorders; however, a molecular understanding of how they initiate infection of their host remains poorly characterized. We demonstrate that trimeric protrusions located at the corners of a single microvirus capsomer mediate host cell attachment. This interaction triggers opening of the capsomer, driven by separation of subunits from its center, much like flower petals open during blooming. This extensive opening explains how the genome translocation apparatus, along with the genome itself, is able to exit the capsid. \"Penton blooming\" likely represents a conserved mechanism shared by diverse viruses possessing similar capsid architectures.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0371324"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Storage of the vital metal tungsten in a dominant SCFA-producing human gut microbe <i>Eubacterium limosum</i> and implications for other gut microbes.","authors":"Nana Shao, Dayong Zhou, Gerrit J Schut, Farris L Poole, Sydney B Coffey, Aaron P Donaghy, Saisuki Putumbaka, Michael P Thorgersen, Lirong Chen, John Rose, Bi-Cheng Wang, Michael W W Adams","doi":"10.1128/mbio.02605-24","DOIUrl":"10.1128/mbio.02605-24","url":null,"abstract":"<p><p>Enzymes containing tungsten rather than the ubiquitous and analogous element molybdenum are prevalent in the human gut microbiome, especifically in microbes that contribute to overall gut health. <i>Eubacterium limosum</i> is a dominant human gut organism whose production of beneficial short-chain fatty acids (SCFAs) from lactate involves tungstoenzymes. Here, we characterized <i>E. limosum</i> Tub, a tungsten storage protein. Tub has a sub-nanomolar affinity for tungstate and contains a single TOBE domain first characterized in a molybdate storage protein. Crystal structures revealed Tub assembles as a hexamer composed of a trimer of dimers, capable of binding eight tungstate oxyanions at two distinct binding sites located at inter-subunit interfaces. Tungstate-saturated Tub exhibited unusually high thermal and chemical stability. Glucose-grown <i>E. limosum</i> accumulates tungsten in Tub and has low levels of two tungstoenzymes, termed WOR1 and FDH, which oxidize aldehydes and formate, respectively. Lactate-grown cells contain high concentrations of these two tungstoenzymes where WOR1 and FDH are involved in converting lactate to SCFAs. Glucose-grown cells appear to accumulate tungstate in Tub in preparation for lactate availability in the human gut. Tub and other TOBE-containing proteins are widespread in the human gut microbiome, and gene co-occurrence analysis predicts that there are comparable numbers of TOBE-containing proteins involved in the storage of tungstate as there are that bind molybdate. The results with <i>E. limosum</i> represent an important step for understanding tungsten storage mechanisms for tungstoenzymes within human gut microbes in general.IMPORTANCETungsten metabolism was found to be prevalent in the human gut microbiome, which is involved in the detoxification of food and antimicrobial aldehydes, as well as in the production of beneficial SCFAs. In this study, we characterized a protein in the human gut microbe, <i>Eubacterium limosum</i>, that stores tungstate in preparation for its use in enzymes involved in SCFA generation. This revealed several families of tungstate binding proteins that are also involved in tungstate transport and tungstate-dependent regulation and are widely distributed in the human gut microbiome. Elucidating how tungsten is stored and transported in the human gut microbes contributes to our understanding of the human gut microbiome and its impact on human health.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0260524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward the consensus of definitions for the phenomena of antifungal tolerance and persistence in filamentous fungi.","authors":"Jorge Amich, Michael Bromley, Gustavo H Goldman, Clara Valero","doi":"10.1128/mbio.03475-24","DOIUrl":"10.1128/mbio.03475-24","url":null,"abstract":"<p><p>Antifungal drug tolerance and persistence are being increasingly recognized in fungal pathogens. Accordingly, more and more research is being carried out to characterize and understand these phenomena. However, the terminology and methodology employed in the fungal community lack consensus, particularly for filamentous fungi, as they present further complexities when compared to single-celled microorganisms. Hence, with the aim to ensure consistency in the literature, in this Perspective article, we propose tailored definitions for tolerance and persistence in filamentous fungi and suggest methods to detect and investigate these phenomena in the laboratory.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0347524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heparanase, a host gene that potently restricts retrovirus transcription.","authors":"Brandon Waxman, Kyle Salka, Uddhav Timilsina, Supawadee Umthong, Deepak Shukla, Spyridon Stavrou","doi":"10.1128/mbio.03252-24","DOIUrl":"10.1128/mbio.03252-24","url":null,"abstract":"<p><p>Heparanase (HPSE) is a heterodimeric β-D-glucuronidase that is critical in mammalian cells for the enzymatic cleavage of membrane-associated heparan sulfate moieties. Apart from its enzymatic function, HPSE has important non-enzymatic functions, which include transcriptional regulation, chromatin modification, and modulation of various signaling pathways. Interestingly, while <i>HPSE</i> is an interferon-stimulated gene, past reports have shown that it has proviral properties for many different viruses, including herpes simplex virus 1, as it assists virus release from infected cells. However, as of yet, no antiviral functions associated with HPSE have been described. Here, we show that HPSE utilizes a hitherto unknown mechanism to restrict retroviruses by targeting the step of proviral transcription. Moreover, we demonstrate that HPSE blocks transcription initiation by targeting the SP1 transcription factor. Finally, we illustrate that the antiretroviral effect of HPSE is independent of its enzymatic activity. This report describes a novel antiviral mechanism utilized by HPSE to inhibit retrovirus infection.IMPORTANCEHeparanase (HPSE) has emerged as an important factor that has proviral functions for a number of viruses, including herpes simplex virus and hepatitis C virus, by assisting in virus egress. However, HPSE is an interferon-stimulated gene and, thus, is a part of the host antiviral defense. Nothing is known about the antiviral functions of HPSE. Here, we examine in depth the role of HPSE during retrovirus infection using two retroviruses, human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus. In this report, we show that mouse, but not human, HPSE blocks retrovirus infection by targeting provirus transcription. HPSE sequesters the SP1 transcription factor away from the proviral promoter, thereby inhibiting transcription initiation. In conclusion, our findings identify a novel antiviral function of HPSE and its potential role as an inhibitor of zoonotic transmission of retroviruses.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0325224"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA gm40262 promotes liver fibrosis and parasite growth through the gm40262-miR-193b-5p-TLR4/Col1α1 axis.","authors":"Tingli Liu, Guiting Pu, Liqun Wang, Ziyu Ye, Hong Li, Rui Li, Yanping Li, Xiaola Guo, William C Cho, Hong Yin, Yadong Zheng, Xuenong Luo","doi":"10.1128/mbio.02287-24","DOIUrl":"10.1128/mbio.02287-24","url":null,"abstract":"<p><p>Alveolar echinococcosis (AE) is a severe and life-threatening parasitic disease caused by <i>Echinococcus multilocularis</i>. Liver fibrosis is a significant pathological feature of advanced AE, characterized by the excessive production and accumulation of extracellular matrix (ECM). However, the precise underlying mechanism remains largely unknown. In this study, we show that the long noncoding RNA gm40262, predominantly expressed in hepatic stellate cells (HSCs), is upregulated in AE. Interestingly, its knockdown leads to liver fibrosis resolution, accompanied by a substantial suppression of parasite growth. Gm40262 functions by targeting miR-193b-5p to activate HSCs and stimulate their proliferation in a TGF-β-dependent manner, thereby promoting ECM production by upregulating Col1α1. Moreover, gm40262 is also involved in inflammation through the gm40262-miR-193b-5p-TLR4 axis. Our findings suggest that gm40262 plays a pivotal role in parasite-induced liver fibrosis through multiple mechanisms, highlighting its potential as a therapeutic target for hepatic fibrosis.</p><p><strong>Importance: </strong><i>Echinococcus multilocularis</i> is a tiny parasite with significant medical implications. The chronic parasitism of <i>E. multilocularis</i> in the liver generally leads to liver fibrosis, but the underlying mechanisms are poorly understood. We herein show that gm40262, a long noncoding RNA predominantly expressed in hepatic stellate cells (HSCs), is involved in hepatic fibrogenesis during infection by activating HSCs and promoting extracellular matrix production. The gm40262-orchestrating fibrogenesis occurs through the gm40262-miR-193b-5p-TLR4 and gm40262-miR-193b-5p-Col1α1 axes. The knockdown of gm40262 remarkably alleviates liver fibrosis, with decreased parasite growth. Our findings reveal a key role of gm40262 in liver fibrosis during <i>E. multilocularis</i> infection, rendering it a therapeutic target for hepatic fibrosis.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0228724"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural compounds target the M23B zinc metallopeptidase Mpg to modulate <i>Neisseria gonorrhoeae</i> Type IV pilus expression.","authors":"Kathleen R Nicholson, Shaohui Yin, Jennifer L Edwards, Chi-Hao Luan, H Steven Seifert","doi":"10.1128/mbio.04027-24","DOIUrl":"10.1128/mbio.04027-24","url":null,"abstract":"<p><p><i>Neisseria gonorrhoeae</i> uses the Type IV pilus (T4p) to colonize several sites within humans by adhering to host cells and tissues. Previously, we identified a periplasmic M23B zinc metallopeptidase, Mpg, that is necessary to protect from oxidative and nonoxidative killing and these phenotypes are mediated by Mpg activities on T4p expression. Here, we use a high-throughput, target-based screening approach to identify novel inhibitors of Mpg's enzymatic activity. We identified two natural compounds, punicalagin and chebulinic acid, which inhibit the peptidoglycan-hydrolyzing activity of Mpg in a dose-dependent manner. Moreover, treatment of <i>N. gonorrhoeae</i> with these compounds leads to a concomitant decrease in the number of T4p, similar to an <i>mpg</i> mutant. However, these compounds are not toxic to <i>N. gonorrhoeae</i>. These compounds exhibit activity against Mpg orthologs from other bacterial species. Notably, these natural compounds inhibit <i>N. gonorrhoeae</i> colonization and survival in cell culture models of infection. This work provides the characterization of two natural compounds with activity against <i>N. gonorrhoeae</i> T4p through the Mpg M23B class zinc metallopeptidase.</p><p><strong>Importance: </strong><i>Neisseria gonorrhoeae</i> is a global health burden with high transmission rates and multidrug resistance. <i>N. gonorrhoeae</i> encodes a Type IV pilus (T4p), which is a major colonization and virulence factor. The importance of the T4p in multiple stages of infection makes it an attractive drug target. Previously, we identified an M23B zinc metallopeptidase, Mpg, important for T4p production and T4p-mediated resistance to neutrophil killing. In this study, we identified two natural compounds, punicalagin and chebulinic acid, as novel inhibitors of Mpg's enzymatic activity that thus inhibit T4p expression. These findings identify two potential anti-colonization and anti-virulence compounds and provide a framework to target T4p components for future screens, poising the field to potentially discover additional compounds to combat <i>N. gonorrhoeae</i> infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0402724"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A call for healing and unity.","authors":"Patrick D Schloss","doi":"10.1128/mbio.00624-25","DOIUrl":"10.1128/mbio.00624-25","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0062425"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}