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BMC Microbiology Jan 2023Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor...
Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses.
Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor hygienic environments. To find novel therapeutic targets and inhibitors, We employed a subtractive genomics strategy towards Salmonella Typhi and the complete genomes of eight strains were primarily subjected to the EDGAR tool to predict the core genome (n = 3207). Human non-homology (n = 2450) was followed by essential genes identification (n = 37). The STRING database predicted maximum protein-protein interactions, followed by cellular localization. The virulent/immunogenic ability of predicted genes were checked to differentiate drug and vaccine targets. Furthermore, the 3D models of the identified putative proteins encoded by the respective genes were constructed and subjected to druggability analyses where only "highly druggable" proteins were selected for molecular docking and simulation analyses. The putative targets ATP-dependent CLP protease proteolytic subunit, Imidazole glycerol phosphate synthase hisH, 7,8-dihydropteroate synthase folP and 2,3-bisphosphoglycerate-independent phosphoglycerate mutase gpmI were screened against a drug-like library (n = 12,000) and top hits were selected based on H-bonds, RMSD and energy scores. Finally, the ADMET properties for novel inhibitors ZINC19340748, ZINC09319798, ZINC00494142, ZINC32918650 were optimized followed by binding free energy (MM/PBSA) calculation for ligand-receptor complexes. The findings of this work are expected to aid in expediting the identification of novel protein targets and inhibitors in combating typhoid Salmonellosis, in addition to the already existing therapies.
Topics: Humans; Anti-Bacterial Agents; Endopeptidase Clp; Genomics; Molecular Docking Simulation; Salmonella typhi; Typhoid Fever
PubMed: 36681806
DOI: 10.1186/s12866-023-02756-6 -
Nature Communications May 2021As whole-genome sequencing capacity becomes increasingly decentralized, there is a growing opportunity for collaboration and the sharing of surveillance data within and...
As whole-genome sequencing capacity becomes increasingly decentralized, there is a growing opportunity for collaboration and the sharing of surveillance data within and between countries to inform typhoid control policies. This vision requires free, community-driven tools that facilitate access to genomic data for public health on a global scale. Here we present the Pathogenwatch scheme for Salmonella enterica serovar Typhi (S. Typhi), a web application enabling the rapid identification of genomic markers of antimicrobial resistance (AMR) and contextualization with public genomic data. We show that the clustering of S. Typhi genomes in Pathogenwatch is comparable to established bioinformatics methods, and that genomic predictions of AMR are highly concordant with phenotypic susceptibility data. We demonstrate the public health utility of Pathogenwatch with examples selected from >4,300 public genomes available in the application. Pathogenwatch provides an intuitive entry point to monitor of the emergence and spread of S. Typhi high risk clones.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Genome, Bacterial; Genomics; Genotype; Geography; Humans; Malawi; Membrane Transport Proteins; Microbial Sensitivity Tests; Mutation; Salmonella typhi; Tanzania; Typhoid Fever
PubMed: 34001879
DOI: 10.1038/s41467-021-23091-2 -
Research in Microbiology 1990In recent years there has been a resurgence of research to develop new and improved attenuated strains of Salmonella typhi to function as live oral vaccines against... (Clinical Trial)
Clinical Trial Comparative Study Review
In recent years there has been a resurgence of research to develop new and improved attenuated strains of Salmonella typhi to function as live oral vaccines against typhoid fever and to serve as "carrier" vaccines to express foreign antigens of other pathogens and deliver them to the immune system. Strain Ty21a has served as a prototype in clinical and field trials to identify the optimal formulations and dosage schedules for live vaccines and to quantitate the duration of protection that can be achieved. Clinical trials with three new attenuated S. typhi candidate vaccines, a Vi+ variant of Ty21a, an aroC,aroD double mutant recombinant strain and a cya,crp double mutant, are underway or will be initiated shortly.
Topics: Administration, Oral; Humans; Mutation; Salmonella typhi; Typhoid-Paratyphoid Vaccines; Vaccines, Attenuated; Vaccines, Synthetic
PubMed: 2101470
DOI: 10.1016/0923-2508(90)90114-6 -
Journal of Infection in Developing... Dec 2008Salmonella enterica serovar Typhi (Typhi), the aetiologic agent of typhoid fever, is a human restricted pathogen. Elucidation of the interactions between the infected... (Review)
Review
Salmonella enterica serovar Typhi (Typhi), the aetiologic agent of typhoid fever, is a human restricted pathogen. Elucidation of the interactions between the infected host and this pathogen is critical to understand infectious diseases but is deterred by a lack of in vivo infection assays, since Typhi uniquely infects humans and there is no suitable animal model. Macrophages can be used as an alternative model, as the ability to survive and replicate within these cells is thought to be one of the major pathogenesis determinants for Salmonella. Typhi genes that are expressed within human macrophages have been identified, as well as Typhi immunogenic proteins expressed in humans with typhoid. Known virulence factors of Salmonella are expressed during infection of macrophages, such as SPI-2 encoded genes, supporting the validity of the model; however, many genes of unknown functions are also expressed. The importance of these genes should be investigated during future studies aimed at elucidating the intracellular lifestyle of this human-specific pathogen. This review describes Typhi genes expressed during infection or involved in cell interaction.
Topics: Gene Expression Regulation, Bacterial; Genes, Bacterial; Host-Pathogen Interactions; Humans; Macrophages; Salmonella typhi; Typhoid Fever; Virulence; Virulence Factors
PubMed: 19745519
DOI: 10.3855/jidc.157 -
BMC Microbiology Jan 2010Typhoid and paratyphoid fever are endemic in China. The objective of this investigation was to determine the molecular features of nalidixic acid-resistant Salmonella...
BACKGROUND
Typhoid and paratyphoid fever are endemic in China. The objective of this investigation was to determine the molecular features of nalidixic acid-resistant Salmonella enteric serovar Typhi (S. typhi) and Paratyphi (S. paratyphi) from blood isolates in Shenzhen, China.
RESULTS
Twenty-five S. typhi and 66 S. paratyphi were isolated from 91 bacteremic patients between 2002 and 2007 at a hospital in Shenzhen, Southern China. Fifty-two percent (13/25) of S. typhi and 95.3% (61/64) of S. paratyphi A were resistant to nalidixic acid. Sixty-seven isolates of nalidixic acid-resistant Salmonella (NARS) showed decreased susceptibility to ciprofloxacin (MICs of 0.125-1 microg/mL). All 75 NARS isolates had a single substitution in the quinolone resistance-determining region (QRDR) of GyrA (Ser83-->Phe/Pro/Tyr, or Asp87-->Gly/Asn), and 90.7% of these isolates carried the substitution Ser83Phe in GyrA. No mutation was found in the QRDR of gyrB, parC, or parE. Plasmid mediated quinolone resistance genes including qnr and aac(6')-Ib-cr were not detected in any isolate. Twenty-two distinct pulsed field gel electrophoresis (PFGE) patterns were observed among S. typhi. Sixty-four isolates of S. paratyphi A belonged to one clone. Eighty-seven investigated inpatients were infected in the community. Six patients infected by S. paratyphi A had a travel history before infection.
CONCLUSIONS
Nalidixic acid-resistant S. typhi and S. paratyphi A blood isolates were highly prevalent in Shenzhen, China. PFGE showed the variable genetic diversity of nalidixic acid-resistant S. typhi and limited genetic diversity of nalidixic acid -resistant S. paratyphi A.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; China; DNA, Bacterial; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Genetic Variation; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Middle Aged; Nalidixic Acid; Paratyphoid Fever; Prevalence; Salmonella paratyphi A; Salmonella typhi; Sequence Analysis, DNA; Typhoid Fever; Young Adult
PubMed: 20113512
DOI: 10.1186/1471-2180-10-32 -
Journal of Bacteriology Jun 2020LtrR is a LysR-type regulator involved in the positive expression of to promote and expression. This regulatory network is fundamental for the control of bacterial...
The Salmonella enterica Serovar Typhi Gene Encodes Two Proteins Whose Transcriptional Expression Is Upregulated by Alkaline pH and Repressed at Their Promoters and Coding Regions by H-NS and Lrp.
LtrR is a LysR-type regulator involved in the positive expression of to promote and expression. This regulatory network is fundamental for the control of bacterial transformation and resistance to the bile salt sodium deoxycholate in serovar Typhi. In this work, the transcriptional regulation of was characterized, revealing that the use of alternative promoters results in two transcripts. The larger one, the mRNA, was repressed at promoter and coding regions by H-NS, whereas Lrp repressed its expression at the coding region. In the case of the second and shorter transcript, it was repressed only at the coding region by H-NS and Lrp. Remarkably, pH 7.5 is a positive signal involved in the transcriptional expression of both units. Translational fusions and Western blot experiments demonstrated that and mRNAs encode the LtrR2 and LtrR1 proteins. This study adds new data on the complex genetic and regulatory characteristics of one of the most predominant types of transcriptional factors in bacteria, the LysR-type transcriptional regulators. The LysR-type transcriptional regulators are present in viruses, archaea, bacteria, and eukaryotic cells. Furthermore, these proteins are the most abundant transcriptional factors in bacteria. Here, we demonstrate that two LysR-type proteins are generated from the gene. These proteins are genetically induced by pH and repressed at the promoter and coding regions by the global regulators H-NS and Lrp. Thus, novel basic aspects of the complex genetic regulation of the LysR-type transcriptional regulators are described.
Topics: Alkalies; Bacterial Proteins; DNA-Binding Proteins; Gene Expression Regulation, Bacterial; Hydrogen-Ion Concentration; Operon; Promoter Regions, Genetic; Salmonella typhi; Transcription Factors
PubMed: 32284321
DOI: 10.1128/JB.00783-19 -
Gut Microbes 2012The host restricts dissemination of invasive enteric pathogens, such as non-typhoidal Salmonella serovars, by mounting acute inflammatory responses characterized by the... (Review)
Review
The host restricts dissemination of invasive enteric pathogens, such as non-typhoidal Salmonella serovars, by mounting acute inflammatory responses characterized by the recruitment of neutrophils. However, some enteric pathogens, such as Salmonella enterica serovar Typhi (S. typhi), can bypass these defenses and cause an invasive bloodstream infection known as typhoid fever. Recent studies on virulence mechanisms of S. typhi suggest that tight regulation of virulence gene expression during the transition from the intestinal lumen into the intestinal mucosa enables this pathogen to evade detection by the innate immune system, thereby penetrating defenses that prevent bacterial dissemination. This example illustrates how the outcome of host pathogen interaction at the intestinal mucosal interface can alter the clinical presentation and dictate the disease outcome.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; Humans; Immune Evasion; Salmonella typhi; Typhoid Fever; Virulence; Virulence Factors
PubMed: 22156762
DOI: 10.4161/gmic.18602 -
Antimicrobial Agents and Chemotherapy Nov 2014We characterized Salmonella enterica serovar Typhi isolates from Bangladesh, Indonesia, Taiwan, and Vietnam to investigate their genetic relatedness and antimicrobial...
We characterized Salmonella enterica serovar Typhi isolates from Bangladesh, Indonesia, Taiwan, and Vietnam to investigate their genetic relatedness and antimicrobial resistance. The isolates from Bangladesh and Vietnam were genetically closely related but were distant from those from Indonesia and Taiwan. All but a few isolates from Indonesia and Taiwan were susceptible to all antimicrobials tested. The majority of isolates from Bangladesh and Vietnam were multidrug resistant (MDR) and belonged to the widespread haplotype H58 clone. IncHI1 plasmids were detected in all MDR S. Typhi isolates from Vietnam but in only 15% of MDR isolates from Bangladesh. Resistance genes in the majority of MDR S. Typhi isolates from Bangladesh should reside in the chromosome. Among the isolates from Bangladesh, 82% and 40% were resistant to various concentrations of nalidixic acid and ciprofloxacin, respectively. Several resistance mechanisms, including alterations in gyrase A, the presence of QnrS, and enhanced efflux pumps, were involved in the reduced susceptibility and resistance to fluoroquinolones. Intensive surveillance is necessary to monitor the spread of chromosome-mediated MDR and fluoroquinolone-resistant S. Typhi emerging in Bangladesh.
Topics: Anti-Bacterial Agents; Bangladesh; Base Sequence; Carrier Proteins; Ciprofloxacin; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Indonesia; Microbial Sensitivity Tests; Nalidixic Acid; Phylogeny; Plasmids; Polymorphism, Single Nucleotide; Salmonella typhi; Sequence Analysis, DNA; Taiwan; Typhoid Fever; Vietnam
PubMed: 25136011
DOI: 10.1128/AAC.03608-14 -
BMC Research Notes Jul 2019Plasmids harbour antibiotic resistance genes which contribute to the emergence of multidrug resistant pathogens. We detected the presence of plasmids in multidrug...
OBJECTIVES
Plasmids harbour antibiotic resistance genes which contribute to the emergence of multidrug resistant pathogens. We detected the presence of plasmids in multidrug resistant Salmonella enterica serovar Typhi (S. Typhi) isolates from our previous study and consequently determined their incompatibility groups and possibility of conjugation transmission. Plasmids were extracted from 98 multidrug resistant S. Typhi isolates based on alkaline lysis technique. Plasmid incompatibility grouping was established by PCR replicon typing using 18 pairs of primers to amplify FIA, FIB, FIC, HI1, HI2, I1-Iγ, L/M, N, P, W, T, A/C, K, B/O, X, Y, F and FIIA replicons. Antibiotic resistance phenotypes were conjugally transferred from S. Typhi isolates with plasmids to Escherichia coli K12F strain devoid of plasmids.
RESULTS
Approximately 79.6% of the MDR S. Typhi isolates were related to the existence of plasmids. We detected 93.6% of plasmids belonging to incompatibility (Inc) group HI1. The other incompatibility groups identified included IncFIC (16.7%), IncP (1.3%), and IncI1 (1.3%) which appeared together with Inc HI1. MDR S. Typhi isolated carried a homologous plasmid of incompatibility group HI1 most of which transferred the resistance phenotypes of ampicillin, tetracycline and chloramphenicol to the transconjugants.
Topics: Ampicillin; Anti-Bacterial Agents; Chloramphenicol; Conjugation, Genetic; Drug Resistance, Multiple, Bacterial; Escherichia coli; Humans; Kenya; Microbial Sensitivity Tests; Plasmids; Replicon; Salmonella typhi; Tetracycline; Typhoid Fever
PubMed: 31311578
DOI: 10.1186/s13104-019-4468-9 -
The Journal of Infectious Diseases Dec 2021In 2016, a whole-genome sequence (WGS)-based genotyping framework (GenoTyphi) was developed and provided a phylogenetically informative nomenclature for lineages of... (Review)
Review
In 2016, a whole-genome sequence (WGS)-based genotyping framework (GenoTyphi) was developed and provided a phylogenetically informative nomenclature for lineages of Salmonella Typhi, the etiological agent of typhoid fever. Subsequent surveillance studies have revealed additional epidemiologically important subpopulations, which require the definition of new genotypes and extension of associated software to facilitate the detection of antimicrobial resistance (AMR) mutations. Analysis of 4632 WGS provide an updated overview of the global S Typhi population structure and genotyping framework, revealing the widespread nature of haplotype 58 ([H58] 4.3.1) genotypes and the diverse range of genotypes carrying AMR mutations.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Genotype; Haplotypes; Humans; Phylogeny; Polymorphism, Single Nucleotide; Salmonella typhi; Typhoid Fever; Whole Genome Sequencing
PubMed: 34453548
DOI: 10.1093/infdis/jiab414