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| Chemical structures of the glycopeptide antibiotics used in study. (A) Natural glycopeptide antibiotics, approved for the clinical use. (B) Semisynthetic lipoglycopeptide antibiotics, approved for the clinical use. (C) Semisynthetic derivatives of teicoplanin pseudoaglycone. (D) Fluorescently labeled vancomycin (FL-Vancomycin) and teicoplanin (FL-Teicoplanin). Lipophilic modifications of the glycopeptide antibiotics are shown in red.
Source publication
vanZ, a member of the VanA glycopeptide resistance gene cluster, confers resistance to lipoglycopeptide antibiotics independent of cell wall precursor modification by the vanHAX genes. Orthologs of vanZ are present in the genomes of many clinically relevant bacteria, including Enterococcus faecium and Streptococcus pneumoniae; however, vanZ genes a...
Contexts in source publication
Context 1
... ability of the E. faecium vanZ Tei and vanZ g paralogs to confer resistance to glycopeptide antibiotics was tested in S. aureus, which naturally does not encode any proteins of the VanZ superfamily. In particular, we determined the susceptibility of S. aureus RN4220 expressing vanZ Tei and vanZ g to the clinically used glycopeptide antibiotic vancomycin (VAN); the lipoglycopeptide antibiotics teicoplanin (TEI), oritavancin (ORI), and dalbavancin (DALB); and three experimental lipoglycopeptide antibiotics derived from teicoplanin pseudoaglycone: MA79 (Csávás et al., 2015), ERJ390 ( Pintér et al., 2009) and SZZS-12 (Szucs et al., 2017; Figure 1). In addition, the non-glycopeptide antibiotics carbenicillin (CARB, cell wall-targeting) gentamicin (GEN, 30S ribosometargeting) and erythromycin (ERY, 50S ribosome-targeting) were used as controls. ...
Context 2
... test whether different levels of protein expression cause different activities of VanZg and VanZTei, we performed Western blot analysis of the strains expressing C-terminal His-tagged versions of VanZ proteins. However, the analysis showed that both proteins were expressed at similar levels and that they were localized exclusively in the cell membrane (Supplementary Figure S1). ...
Similar publications
We determined the clinical and molecular epidemiology of emerging nosocomial vancomycin-resistant Enterococcus faecium (VREfm)–causing serious bloodstream infections (BSIs) and the correlations between antibiotic resistance and virulence determinants among isolates. All isolates were confirmed by molecular methods (16SrRNA and E. faecium ddl genes)...
Citations
... While our interpretations are somewhat limited by incomplete assembly, this could result from the shedding of unnecessary genes upon transitioning to oligotrophic groundwaters scarce in energy sources. The annotated genes, unique to the seepage Parcubacteria C7867-001 and genetically related MAGs isolated from the same source, encode a diacylglycerol kinase, a membrane protein known to play a key role in phospholipid metabolism and bacterial survival under variable osmotic conditions [56], and an antibiotic resistance protein that prevents the binding of lipoglycopeptide antibiotics [57]. The nitrite reductase gene (nirK, K00368) was unique to groundwater Parcubacterium and its neighboring Parcubacteria from groundwater in the phylogenetic tree (Additional file 2: Table S9) likely in response to local exposures to nitrate and/or nitrite. ...
Background
To better understand the influence of habitat on the genetic content of bacteria, with a focus on members of Candidate Phyla Radiation (CPR) bacteria, we studied the effects of transitioning from soil via seepage waters to groundwater on genomic composition of ultra-small Parcubacteria , the dominating CPR class in seepage waters, using genome resolved metagenomics.
Results
Bacterial metagenome-assembled genomes (MAGs), (318 total, 32 of Parcubacteria ) were generated from seepage waters and compared directly to groundwater counterparts. The estimated average genome sizes of members of major phyla Proteobacteria , Bacteroidota and Cand . Patescibacteria (Candidate Phyla Radiation – CPR bacteria) were significantly higher in soil-seepage water as compared to their groundwater counterparts. Seepage water Parcubacteria ( Paceibacteria ) exhibited 1.18-fold greater mean genome size and 2-fold lower mean proportion of pseudogenes than those in groundwater. Bacteroidota and Proteobacteria also showed a similar trend of reduced genomes in groundwater compared to seepage. While exploring gene loss and adaptive gains in closely related CPR lineages in groundwater, we identified a membrane protein, and a lipoglycopeptide resistance gene unique to a seepage Parcubacterium genome. A nitrite reductase gene was also identified and was unique to the groundwater Parcubacteria genomes, likely acquired from other planktonic microbes via horizontal gene transfer.
Conclusions
Overall, our data suggest that bacteria in seepage waters, including ultra-small Parcubacteria , have significantly larger genomes and higher metabolic enrichment than their groundwater counterparts, highlighting possible genome streamlining of the latter in response to habitat selection in an oligotrophic environment.
... Generally, vancomycin resistant bacterial strain adjusts its cell wall biosynthesis pathway to get away from inhibitory effects of this antibiotic. However, VanZ mediated molecular mechanism of antibiotic resistance is not deciphered properly so far (Vimberg et al., 2020). Another amino glycoside group of antibiotics resistance protein, GNAT family N-acetyltransferase is also situated within GI-2. ...
In this study, arsenic tolerating bacteria Bacillus pacificus(AKS1a) was isolated from arsenic contaminated groundwater of Purbasthali, Purba Bardhaman, West Bengal, India and its bioremediation potential was preliminary screened. This multimetal resistant strain was able to grow against more than 20 mM arsenate and 10 mM arsenite salts. The genome was more than 5.16 Mb in length, with an average of around 35.2% GC content, bearing 5403 protein coding genes. Arsenic resistant genes like arsC, arsB, arsR, etc. were also identified. Rapid Annotation using Subsystem Technology (RAST) identified 328 subsystems within the genome. Presence of six Genomic Islands (GIs) and five phage virus genomic parts indicated its ecological adaptations to overcome environmental stresses. The production of about 415 μg mL−1 indole acetic acid (IAA), 258.0 μg mL−1 gibberellic acid (GA), and 183 μg mL−1 proline by the bacterium, along with nitrogen fixation ability under in-vitro conditions, indicate its plant growth promoting potential. This was further confirmed through rice seedling growth enhancement under arsenic stress. Beside arsenite oxidation to arsenate, its arsenic adsorption property was confirmed through X-ray Fluorescence spectroscopy (XRF), Fourier Transform Infrared spectroscopy (FTIR), and Energy Dispersive X-ray spectroscopic (EDS) Analysis. Genomic comparisons among 25 different strains of B. pacificus showed that there are tremendous genetic differences in respect to their accessory genome content. In future, this strain can be applied as biofertilizer or biostimulant for improving rice plant growth.
... VanZ is an accessory protein that protects bacteria from glycopeptide antibiotics by affecting their binding to cell surfaces ( Figure 4). 93,94 The expression of vanA operon is mainly regulated by the VanSR two-component transduction system. VanS, as a sensor, is a membrane-bound histidine kinase involved in signal transduction. ...
Zhuru Hou,1,2,* Ling Liu,2– 4,* Jianhong Wei,1 Benjin Xu2– 4 1Department of Basic Medicine, Fenyang College of Shanxi Medical University, Fenyang, People’s Republic of China; 2Key Laboratory of Lvliang for Clinical Molecular Diagnostics, Fenyang, People’s Republic of China; 3Department of Medical Laboratory Science, Fenyang College of Shanxi Medical University, Fenyang, People’s Republic of China; 4Department of Clinical Laboratory, Fenyang Hospital of Shanxi Province, Fenyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhong Wei, Department of Basic Medicine, Fenyang College of Shanxi Medical University, Fenyang, 032200, People’s Republic of China, Email wjh5123@163.com Benjin Xu, Department of Medical Laboratory Science, Fenyang College of Shanxi Medical University, Fenyang, 032200, People’s Republic of China, Email bj0726@sxmu.edu.cnAbstract: Staphylococcus aureus is a common human pathogen with a variety of virulence factors, which can cause multiple infectious diseases. In recent decades, due to the constant evolution and the abuse of antibiotics, Staphylococcus aureus was becoming more resistant, the infection rate of MRSA remained high, and clinical treatment of MRSA became more difficult. The genetic diversity of MRSA was mainly represented by the continuous emergence of epidemic strains, resulting in the constant changes of epidemic clones. Different classes of MRSA resulted in different epidemics and resistance characteristics, which could affect the clinical symptoms and treatments. MRSA had also spread from traditional hospitals to community and livestock environments, and the new clones established a relationship between animals and humans, promoting further evolution of MRSA. Since the resistance mechanism of MRSA is very complex, it is important to clarify these resistance mechanisms at the molecular level for the treatment of infectious diseases. We firstly described the diversity of SCCmec elements, and discussed the types of SCCmec, its drug resistance mechanisms and expression regulations. Then, we described how the vanA operon makes Staphylococcus aureus resistant to vancomycin and its expression regulation. Finally, a brief introduction was given to the drug resistance mechanisms of biofilms and efflux pump systems. Analyzing the resistance mechanism of MRSA can help study new anti-infective drugs and alleviate the evolution of MRSA. At the end of the review, we summarized the treatment strategies for MRSA infection, including antibiotics, anti-biofilm agents and efflux pump inhibitors. To sum up, here we reviewed the epidemic characteristics of Staphylococcus aureus, summarized its classifications, drug resistance mechanisms of MRSA (SCCmec element, vanA operon, biofilm and active efflux pump system) and novel therapy strategies, so as to provide a theoretical basis for the treatment of MRSA infection.Keywords: biofilm, efflux pump, MRSA, prevalence, resistance mechanism, SCCmec
... 108,109 We further identified the antibiotic resistance protein VanZ (MSR16_hyp_778 and MSR17_hyp_703), which reduces the binding of lipoglycopeptide antibiotics to cell wall components, resulting in resistance to teicoplanin and vancomycin antibiotics. 110,111 Toxin proteins and toxin transporters. The thermostable direct hemolysin (TDH) and the TDH related hemolysin (TRH) are both regarded to be key virulence factors in pathogenic strains of the bacteria V. parahaemolyticus. ...
Vibrio parahaemolyticus, an aquatic pathogen, is a major concern in the shrimp aquaculture industry. Several strains of this pathogen are responsible for causing acute hepatopancreatic necrosis disease as well as other serious illness, both of which result in severe economic losses. The genome sequence of two pathogenic strains of V. parahaemolyticus, MSR16 and MSR17, isolated from Bangladesh, have been reported to gain a better understanding of their diversity and virulence. However, the prevalence of hypothetical proteins (HPs) makes it challenging to obtain a comprehensive understanding of the pathogenesis of V. parahaemolyticus. The aim of the present study is to provide a functional annotation of the HPs to elucidate their role in pathogenesis employing several in silico tools. The exploration of protein domains and families, similarity searches against proteins with known function, gene ontology enrichment, along with protein-protein interaction analysis of the HPs led to the functional assignment with a high level of confidence for 656 proteins out of a pool of 2631 proteins. The in silico approach used in this study was important for accurately assigning function to HPs and inferring interactions with proteins with previously described functions. The HPs with function predicted were categorized into various groups such as enzymes involved in small-compound biosynthesis pathway, iron binding proteins, antibiotics resistance proteins, and other proteins. Several proteins with potential druggability were identified among them. In addition, the HPs were investigated in search of virulent factors, which led to the identification of proteins that have the potential to be exploited as vaccine candidate. The findings of the study will be effective in gaining a better understanding of the molecular mechanisms of bacterial pathogenesis. They may also provide an insight into the process of evaluating promising targets for the development of drugs and vaccines against V. parahaemolyticus.
... The genome of Lc. paracasei SP5 carries the resistance genes vanR and vanZ. The mechanism of action of VanZ remains unknown, however, there are indications that it can exclude vancomycin and other lipoglycopeptide antibiotics from the cell wall, increasing the minimum inhibitory concentration required (Vimberg et al., 2020). VanR is a response element that activates transcription of the vanHAX cluster after vancomycin exposure. ...
The Lacticaseibacillus paracasei species is comprised by nomadic bacteria inhabiting a wide variety of ecological niches, from fermented foodstuffs to host-associated microenvironments. Lc. paracasei SP5 is a novel strain, originally isolated from kefir grains that presents desirable probiotic and biotechnological attributes. In this study, we applied genomic tools to further characterize the probiotic and biotechnological potential of the strain. Firstly, whole genome sequencing and assembly, were performed to construct the chromosome map of the strain and determine its genomic stability. Lc. paracasei SP5 carriers several insertion sequences, however, no plasmids or mobile elements were detected. Furthermore, phylogenomic and comparative genomic analyses were utilized to study the nomadic attributes of the strain, and more specifically, its metabolic capacity and ability to withstand environmental stresses imposed during food processing and passage through the gastrointestinal (GI) tract. More specifically, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Carbohydrate-active enzyme (CAZymes) analyses provided evidence for the ability of the stain to utilize an array of carbohydrates as growth substrates. Consequently, genes for heat, cold, osmotic shock, acidic pH, and bile salt tolerance were annotated. Importantly bioinformatic analysis showed that the novel strain does not harbor acquired antimicrobial resistance genes nor virulence factors, in agreement with previous experimental data. Putative bacteriocin biosynthesis clusters were identified using BAGEL4, suggesting its potential antimicrobial activity. Concerning microbe-host interactions, adhesins, moonlighting proteins, exopolysaccharide (EPS) biosynthesis genes and pilins mediating the adhesive phenotype were, also, pinpointed in the genome of Lc. paracasei SP5. Validation of this phenotype was performed by employing a microbiological method and confocal microscopy. Conclusively, Lc. paracasei SP5 harbors genes necessary for the manifestation of the probiotic character and application in the food industry. Upcoming studies will focus on the mechanisms of action of the novel strain at multiple levels.
... Of note, the genome content analysis also revealed a vanZ-like domain, known to be present in the genomes of clinically relevant bacteria, such as Bacillus, Streptococcus, Enterococcus, and Clostridium, and decreases their sensitivity to some lipoglycopeptide antibiotics, but not vancomycin [37,38]. Non-chromosomal genomic content in our isolates is represented by the plasmid pUC11C (Table 2) [39], known to encode two class C sortases, which are commonly involved in pilus biosynthesis [40,41]. ...
... We also identified chromosomal contents conferring drug resistance to lincosamides (IsaD gene) and penicillins (penicillin binding proteins) ( Table 2), and to some lipoglycopeptide antibiotics [31,35,37,38,57], thus providing the genetic basis of the antimicrobial susceptibility testing results, that defined resistance to clindamycin and intermediate resistance to penicillin G. These results also confirmed the drug-resistant genetic backbone of the L. garvieae isolated in the three pediatric patients. ...
Due to an increasing number of infections in adults, Lactococcus (L.) garvieae has gained recognition as an emerging human pathogen, causing bacteraemia and septicaemia.In September 2020, four paediatric onco-hematologic patients received a platelet concentrate from the same adult donor at Bambino Gesù Children's Hospital IRCCS, Rome. Three of four patients experienced L. garvieae sepsis one day after transfusion.The L. garvieae pediatric isolates and the donor's platelet concentrate were retrospectively collected for whole-genome sequencing and shot-gun metagenomics, respectively (Illumina HiSeq). By de novo assembly of the L. garvieae genomes, we found that all three pediatric isolates shared a 99.9% identity and were characterized by 440 common SNPs. Plasmid pUC11C (conferring virulence properties) and the temperate prophage Plg-Tb25 were detected in all three strains. Core SNP genome-based Maximum Likelihood and Bayesian trees confirmed their phylogenetic common origin and revealed their relationship with L. garvieae strains affecting cows and humans (bootstrap values >100 and posterior probabilities = 1.00). Bacterial reads obtained by the donor's platelet concentrate have been profiled with MetaPhlAn2 (v.2.7.5); among these, 29.9% belonged to Firmicutes, and 5.16% to Streptococcaceae (>97% identity with L. garvieae), confirming the presence of L. garvieae in the platelet concentrate transfusion.These data showed for the first time three episodes of sepsis due to a transfusion-associated transmission of L. garvieae in three pediatric hospitalized hematology patients. This highlights the importance to implement the screening of platelet components with new human defined pathogens for ensuring safety of blood supply, and, more broadly, for surveillance of emerging pathogens.
... Importantly, these mechanisms of resistance are shared with teicoplanin in enterococci; hence, these isolates display cross-resistance between the two compounds. In addition, the vanZ gene (a member of the van cluster) has also been shown to contribute to teicoplanin and oritavancin resistance via unknown mechanisms (37)(38)(39). VanZ is a large family of transmembrane proteins whose orthologs are found in genomes of other clinically relevant bacteria, such as Bacillus spp., Streptococcus spp., Enterococcus spp., and Clostridium difficile (40)(41)(42). Remarkably, the expression of vanZ paralogs resulted in increased MICs to oritavancin, dalbavancin, and teicoplanin in S. aureus and Streptococcus pneumoniae (39). ...
... VanZ is a large family of transmembrane proteins whose orthologs are found in genomes of other clinically relevant bacteria, such as Bacillus spp., Streptococcus spp., Enterococcus spp., and Clostridium difficile (40)(41)(42). Remarkably, the expression of vanZ paralogs resulted in increased MICs to oritavancin, dalbavancin, and teicoplanin in S. aureus and Streptococcus pneumoniae (39). Moreover, as part of the van gene cluster, vanZ can be transferred from enterococci to S. aureus, leading to high-level vancomycin-resistant S. aureus strains (43)(44)(45). ...
The long-acting lipoglycopeptides (LGPs) dalbavancin and oritavancin are semisynthetic antimicrobials with broad and potent activity against Gram-positive bacterial pathogens. While they are approved by the Food and Drug Administration for acute bacterial skin and soft tissue infections, their pharmacological properties suggest a potential role of these agents for the treatment of deep-seated and severe infections, such as bloodstream and bone and joint infections. The use of these antimicrobials is particularly appealing when prolonged therapy, early discharge, and avoidance of long-term intravascular catheter access are desirable or when multidrug-resistant bacteria are suspected. This review describes the current evidence for the use of oritavancin and dalbavancin in the treatment of invasive infections, as well as the hurdles that are preventing their optimal use. Moreover, this review discusses the current knowledge gaps that need to be filled to understand the potential role of LGPs in highly needed clinical scenarios and the ongoing clinical studies that aim to address these voids in the upcoming years.
... The exposure of these strains to the G3K did not affect bacterial growth ( Figure S9). Next, the G3K activity on VanZ was checked in vivo, using S. aureus RN4220 strain, with the heterologous expression of VanZ [22]. S. aureus does not contain vanZ in the genome. ...
... G3K itself had no independent antibacterial activity on bacterial growth under laboratory growth conditions, whether the VanZ was encoded in the genome of the bacteria or not. This is in good agreement with previous results that demonstrated no effect of vanZ knockout in S. pneumoniae of vanZ heterologous overexpression in S. aureus on bacterial growth [22]. However, G3K managed to increase the efficiency of TEI against clinical isolate E. faecium, encoding vanZ in the vanA resistance gene cluster, and significantly decrease resistance to TEI in S. pneumoniae, encoding vanZ in its genome. ...
... The in vivo results suggested that G3K was an effective inhibitor of not only VanZ encoded in the vanA glycopeptide antibiotics resistance gene cluster, but also of VanZ encoded in the S. pneumoniae genome. These VanZ proteins are not conserved in the amino acid sequence; however, these proteins have a similar membrane topology with five transmembrane domains [22]. This suggests that independently of the VanZ origin, the mode of action of the proteins can be the same, at least in relation to the lypoglycopeptide antibiotic resistance, and both types of VanZ can be inhibited by G3K. ...
Teicoplanin is a natural lipoglycopeptide antibiotic with a similar activity spectrum as vancomycin; however, it has with the added benefit to the patient of low cytotoxicity. Both teicoplanin and vancomycin antibiotics are actively used in medical practice in the prophylaxis and treatment of severe life-threatening infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, Enterococcus faecium and Clostridium difficile. The expression of vancomycin Z (vanZ), encoded either in the vancomycin A (vanA) glycopeptide antibiotic resistance gene cluster or in the genomes of E. faecium, as well as Streptococcus pneumoniae and C. difficile, was shown to specifically compromise the antibiotic efficiency through the inhibition of teicoplanin binding to the bacterial surface. However, the exact mechanisms of this action and protein structure remain unknown. In this study, the three-dimensional structure of VanZ from E. faecium EnGen0191 was predicted by using the I-TASSER web server. Based on the VanZ structure, a benzimidazole based ligand was predicted to bind to the VanZ by molecular docking. Importantly, this new ligand, named G3K, was further confirmed to specifically inhibit VanZ-mediated resistance to teicoplanin in vivo.
... Previous studies have reported RNase H1/viroplasmin domain-containing protein associated with Caulimovirus (Volovitch et al., 1990), whereas the role of the similar protein in bacteria is not reported so far. The vanZ protein is associated with teicoplanin resistance and the gene orthologs have been reported from several bacterial genera (Vimberg et al., 2020). A previous study has shown clinical resistance to vancomycin in two strains recovered from clinical cases (Aldape et al., 2018). ...
... Previous studies have reported RNase H1/viroplasmin domain-containing protein associated with Caulimovirus (Volovitch et al., 1990), whereas the role of the similar protein in bacteria is not reported so far. The vanZ protein is associated with teicoplanin resistance and the gene orthologs have been reported from several bacterial genera (Vimberg et al., 2020). A previous study has shown clinical resistance to vancomycin in two strains recovered from clinical cases (Aldape et al., 2018). ...
Clostridium septicum is a Gram-positive, toxin-producing, and spore-forming bacterium that is recognized, together with C. perfringens, as the most important etiologic agent of progressive gas gangrene. Clostridium septicum infections are almost always fatal in humans and animals. Despite its clinical and agricultural relevance, there is currently limited knowledge of the diversity and genome structure of C. septicum. This study presents the complete genome sequence of C. septicum DSM 7534T type strain as well as the first comparative analysis of five C. septicum genomes. The taxonomy of C. septicum, as revealed by 16S rRNA analysis as well as by genomic wide indices such as protein-based phylogeny, average nucleotide identity, and digital DNA–DNA hybridization indicates a stable clade. The composition and presence of prophages, CRISPR elements and accessory genetic material was variable in the investigated genomes. This is in contrast to the limited genetic variability described for the phylogenetically and phenotypically related species Clostridium chauvoei. The restriction-modification (RM) systems between two C. septicum genomes were heterogeneous for the RM types they encoded. C. septicum has an open pangenome with 2,311 genes representing the core genes and 1,429 accessory genes. The core genome SNP divergence between genome pairs varied up to 4,886 pairwise SNPs. A vast arsenal of potential virulence genes was detected in the genomes studied. Sequence analysis of these genes revealed that sialidase, hemolysin, and collagenase genes are conserved compared to the α-toxin and hyaluronidase genes. In addition, a conserved gene found in all C. septicum genomes was predicted to encode a leucocidin homolog (beta-channel forming cytolysin) similar (71.10% protein identity) to Clostridium chauvoei toxin A (CctA), which is a potent toxin. In conclusion, our results provide first, valuable insights into strain relatedness and genomic plasticity of C. septicum and contribute to our understanding of the virulence mechanisms of this important human and animal pathogen.
