Computational design of peptide vaccine against Acinetobacter baumannii infection using comparative genomic approach (original) (raw)
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Iranian Journal of Allergy, Asthma and Immunology
Acinetobacter baumannii is a Gram-negative bacterium that has recently been identified as a leading nosocomial pathogen. Infections by this pathogen result in significant mortality due to antibiotic resistance. An effective vaccine would help alleviate the burden of disease incurred by this pathogen; however, there are currently no licensed vaccines offering protection against Acinetobacter baumannii infection. In this study, considering the fact that outer membrane protein A is one of the most promising vaccine candidates, we predicted T cell and B cell epitopes on this protein using sequence-based epitope prediction tools and determined whether or not mice immunized with these peptides induce an immune response. We selected consensus epitopes including five peptides in different tools with the highest score. 48 female C5BL/6 SPF injected subcutaneously with the peptides (peptide1 to peptide 5 separately) in 100 μL of the solution and sham groups received adjuvant and PBS alone on ...
BMC Genomics, 2016
Background: Acinetobacter baumannii has emerged as a significant nosocomial pathogen during the last few years, exhibiting resistance to almost all major classes of antibiotics. Alternative treatment options such as vaccines tend to be most promising and cost effective approaches against this resistant pathogen. In the current study, we have explored the pan-genome of A. baumannii followed by immune-proteomics and reverse vaccinology approaches to identify potential core vaccine targets. Results: The pan-genome of all available A. baumannii strains (30 complete genomes) is estimated to contain 7,606 gene families and the core genome consists of 2,445 gene families (~32 % of the pan-genome). Phylogenetic tree, comparative genomic and proteomic analysis revealed both intra-and inter genomic similarities and evolutionary relationships. Among the conserved core genome, thirteen proteins, including P pilus assembly protein, pili assembly chaperone, AdeK, PonA, OmpA, general secretion pathway protein D, FhuE receptor, Type VI secretion system OmpA/MotB, TonB dependent siderophore receptor, general secretion pathway protein D, outer membrane protein, peptidoglycan associated lipoprotein and peptidyl-prolyl cis-trans isomerase are identified as highly antigenic. Epitope mapping of the target proteins revealed the presence of antigenic surface exposed 9-mer T-cell epitopes. Protein-protein interaction and functional annotation have shown their involvement in significant biological and molecular processes. The pipeline is validated by predicting already known immunogenic targets against Gram negative pathogen Helicobacter pylori as a positive control. Conclusion: The study, based upon combinatorial approach of pan-genomics, core genomics, proteomics and reverse vaccinology led us to find out potential vaccine candidates against A. baumannii. The comprehensive analysis of all the completely sequenced genomes revealed thirteen putative antigens which could elicit substantial immune response. The integration of computational vaccinology strategies would facilitate in tackling the rapid dissemination of resistant A.baumannii strains. The scarcity of effective antibiotics and the global expansion of sequencing data making this approach desirable in the development of effective vaccines against A. baumannii and other bacterial pathogens.
Vaccinomics to Design a Multi-Epitopes Vaccine for Acinetobacter baumannii
International Journal of Environmental Research and Public Health
Antibiotic resistance (AR) is the result of microbes’ natural evolution to withstand the action of antibiotics used against them. AR is rising to a high level across the globe, and novel resistant strains are emerging and spreading very fast. Acinetobacter baumannii is a multidrug resistant Gram-negative bacteria, responsible for causing severe nosocomial infections that are treated with several broad spectrum antibiotics: carbapenems, β-lactam, aminoglycosides, tetracycline, gentamicin, impanel, piperacillin, and amikacin. The A. baumannii genome is superplastic to acquire new resistant mechanisms and, as there is no vaccine in the development process for this pathogen, the situation is more worrisome. This study was conducted to identify protective antigens from the core genome of the pathogen. Genomic data of fully sequenced strains of A. baumannii were retrieved from the national center for biotechnological information (NCBI) database and subjected to various genomics, immunoinf...
European Journal of Pharmaceutical Sciences, 2019
Global emergence of Tigecycline resistant Acinetobacter baumannii (TRAB) is on the horizon and poses a very serious threat to human health. There is a pressing demand for suitable therapeutics against this pathogen, particularly a vaccine to protect against TRAB infections. We present a comprehensive investigation of the complete proteome of a TRAB AB031 strain to predict promiscuous antigenic, non-allergenic, virulent B-cell derived T-cell epitopes and formulate a multi-epitope vaccine against the pathogen. We identified epitopes from three proteins: outer membrane protein assembly factor (BamA), fimbrial biogenesis outer membrane usher protein (FimD) and type IV secretion protein (Rhs) that are appropriate for vaccine design. These proteins constitute the core proteome of the pathogen, are essential, localized at the pathogen surface, non-homologous to humans, mice and to the beneficial probiotic bacteria that reside the human gut. Moreover, these proteins are ideal candidates for experimental investigation as they have favorable physicochemical properties and have strong cellular interacting networks. The predicted epitopes: FPLNDKPGD (BamA), FVHAEEAAA (FimD) and YVVAGTAAA (Rhs) have exo-membrane topology for efficient recognition of the host immune system and high affinity for the most prevalent allele in human populations, the DRB*0101. These epitopes were linked and attached to an adjuvant to enhance its antigenicity. The multi-epitope vaccine-construct was docked with the TLR4 receptor to assess its affinity for the protein and thus its presentation to the host immune system. Docking results were validated through molecular dynamics simulations and binding free energies were calculated using the molecular mechanics/generalized Born (MM-GBSA) method. In conclusion, we expect the designed chimeric vaccine is highly likely to be effective against infections caused by TRAB.
Vaccine Research, 2017
Introduction: Acinetobacter baumannii as a Gram-negative coccobacillus has become a major cause of hospital-acquired infections. The virulence factors involved in serum resistance are important targets in the development of an effective vaccine against this pathogen. Our aim in this project was in silico analyses of A. baumannii proteins involved in serum resistance which could potentially be used as efficient vaccines. Methods: Based on computational procedures, we evaluated all A. baumannii proteins involved in serum resistance, namely AbOmpA, PKF, PLD, PBP 7/8, CipA and Tuf SurA1, as vaccine candidates. Subcellular localization, sequence conservation, domain prediction and 3D modelings were analyzed by online tools. Moreover, the prevalence of serum resistance factors in 5 strains of A. baumannii was characterized. The MHC-binding sites of class I and II were detected. Linear and conformational B cell epitopes were analyzed by 2 prediction servers. Results: The MetaLocGramN server showed that AbOmpA, PKF, PBP7/8, phospholipase D, CipA, Tuf and SurA1 were outer membrane protein (56.32%), extracellular protein (58.74%), extracellular protein (52.59%), cytoplasmic protein (45.08%), extracellular protein (53.8%), Cytoplasmic protein (96.36%) and extracellular protein (58.23%), respectively. The OMD of AbOmpA, PKF, PBP7/8 and phospholipase D, CipA, Tuf and SurA1 were 0.060, 0.076, 0.08, 0.101, 0.09, 0.06 and 0.103, respectively. The numbers of immunogenic linear and conformational epitopes with high score (P ≥ 0.6), extracted from beta-barrel of AbOmpA were 6 and 4; whereas these values for PKF were 10 and 4, respectively. Conclusion: The in silico analyses and reverse vaccinology criteria showed that AbOmpA and PKF had better attributes as vaccine targets and they could be considered as promising vaccine candidates against A. baumannii.
Frontiers in Cellular and Infection Microbiology
Nosocomial infections have become alarming with the increase of multidrug-resistant bacterial strains of Acinetobacter baumannii. Being the causative agent in ∼80% of the cases, these pathogenic gram-negative species could be deadly for hospitalized patients, especially in intensive care units utilizing ventilators, urinary catheters, and nasogastric tubes. Primarily infecting an immuno-compromised system, they are resistant to most antibiotics and are the root cause of various types of opportunistic infections including but not limited to septicemia, endocarditis, meningitis, pneumonia, skin, and wound sepsis and even urinary tract infections. Conventional experimental methods including typing, computational methods encompassing comparative genomics, and combined methods of reverse vaccinology and proteomics had been proposed to differentiate and develop vaccines and/or drugs for several outbreak strains. However, identifying proteins suitable enough to be posed as drug targets and/or molecular vaccines against the multidrug-resistant pathogenic bacterial strains has probably remained an open issue to address. In these cases of novel protein identification, the targets either are uncharacterized or have been unable to confer the most coveted protection either in the form of molecular vaccine candidates or as drug targets. Here, we report a strategic approach with the 3,766 proteins from the whole genome of A. baumannii ATCC19606 (AB) to rationally identify plausible candidates and propose them as future molecular vaccine candidates and/or drug targets. Essentially, we started with mapping the vaccine candidates (VaC) and virulence factors (ViF) of A. baumannii strain AYE onto strain ATCC19606 to identify them in the latter. We move on to build small networks of VaC and ViF to conceptualize their position in the network space of the whole genomic protein interactome (GPIN) and rationalize their candidature for drugs and/or molecular vaccines. To this end, we propose new sets of known proteins Mujawar et al. Vaccine Candidates and Drug Targets of A. baumannii unearthed from interactome built using key factors, KeF, potent enough to compete with VaC and ViF. Our method is the first of its kind to propose, albeit theoretically, a rational approach to identify crucial proteins and pose them for candidates of vaccines and/or drugs effective enough to combat the deadly pathogenic threats of A. baumannii.
2021
Acinetobacter baumannii (A. baumannii), an opportunistic, gram-negative pathogen, has evoked the interest of the medical community throughout the world because of its ability to cause nosocomial infections, majorly infecting those in intensive care units. It has also drawn the attention of researchers due to its evolving immune evasion strategies and increased drug resistance. The emergence of multi-drug-resistant-strains has urged the need to explore novel therapeutic options as an alternative to antibiotics. Due to the upsurge in antibiotic resistance mechanisms exhibited by A. baumannii, the current therapeutic strategies are rendered less effective. The aim of this study is to explore novel therapeutic alternatives against A. baumannii to control the ailed infection. In this study, a computational framework is employed involving, pan genomics, subtractive proteomics and reverse vaccinology strategies to identify core promiscuous vaccine candidates. Two chimeric vaccine construct...
Identification of Novel Vaccine Candidates against Multidrug-Resistant Acinetobacter baumannii
PLoS ONE, 2013
Acinetobacter baumannii is an emerging opportunistic bacterium associated with nosocomial infections in intensive care units. The alarming increase in infections caused by A. baumannii is strongly associated with enhanced resistance to antibiotics, in particular carbapenems. This, together with the lack of a licensed vaccine, has translated into significant economic, logistic and health impacts to health care facilities. In this study, we combined reverse vaccinology and proteomics to identify surface-exposed and secreted antigens from A. baumannii. Using in silico prediction tools and comparative genome analysis in combination with in vitro proteomic approaches, we identified 42 antigens that could be used as potential vaccine targets. Considering the paucity of effective antibiotics available to treat multidrug-resistant A. baumannii infections, these vaccine targets may serve as a framework for the development of a broadly protective multi-component vaccine, an outcome that would have a major impact on the burden of A. baumannii infections in intensive care units across the globe.
Medicina
Background and Objectives: The BaeR protein is involved in the adaptation system of A. baumannii and is associated with virulence factors responsible for systemic infections in hospitalized patients. This study was conducted to characterize putative epitope peptides for the design of vaccines against BaeR protein, using an immune-informatic approach. Materials and Methods: FASTA sequences of BaeR from five different strains of A. baumannii were retrieved from the UNIPROT database and evaluated for their antigenicity, allergenicity and vaccine properties using BepiPred, Vaxijen, AlgPred, AntigenPro and SolPro. Their physio-chemical properties were assessed using the Expasy Protparam server. Immuno-dominant B-cell and T-cell epitope peptides were predicted using the IEDB database and MHC cluster server with a final assessment of their interactions with TLR-2. Results: A final selection of two peptide sequences (36aa and 22aa) was made from the 38 antigenic peptides. E1 was considered ...
Microbial pathogenesis, 2017
Outer membrane protein A (OmpA) is the most promising vaccine candidate against one of the most successful nosocomial pathogens, A. baumannii. Despite advantages of the antigen, its cytotoxicity could be considered as a challenge in clinical trials. In order to improve this effective immunogen, rational vaccine design strategies such as structure-based vaccinology should be assessed. However, native structure of OmpA remains controversial. The present study is conducted to address the native structure of OmpA; then, a novel immunogen with lower toxicity and higher antigenicity was designed based on structural vaccinology. Various bioinformatic and immunoinformatic tools were harnessed to perform analyses such as topology, secondary structure, and tertiary structure predictions as well as B-cell epitope predictions. A novel 12-stranded model is suggested for OmpA. K320 and K322 were substituted by Alanine, "NADEEFWN" sequence was replaced by "YKYDFDGVNRGTRGTSEEGTL"...