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Identification of Biomarkers for the Accurate and Sensitive Diagnosis Of Bakare et al. BMC Molecular and Cell Biology (2020) 21:82 BMC Molecular and https://doi.org/10.1186/s12860-020-00328-4 Cell Biology RESEARCH ARTICLE Open Access Identification of biomarkers for the accurate and sensitive diagnosis of three bacterial pneumonia pathogens using in silico approaches Olalekan Olanrewaju Bakare1,2* , Marshall Keyster2 and Ashley Pretorius1 Abstract Background: Pneumonia ranks as one of the main infectious sources of mortality among kids under 5 years of age, killing 2500 a day; late research has additionally demonstrated that mortality is higher in the elderly. A few biomarkers, which up to this point have been distinguished for its determination lack specificity, as these biomarkers fail to build up a differentiation between pneumonia and other related diseases, for example, pulmonary tuberculosis and Human Immunodeficiency Infection (HIV). There is an inclusive global consensus of an improved comprehension of the utilization of new biomarkers, which are delivered in light of pneumonia infection for precision identification to defeat these previously mentioned constraints. Antimicrobial peptides (AMPs) have been demonstrated to be promising remedial specialists against numerous illnesses. This research work sought to identify AMPs as biomarkers for three bacterial pneumonia pathogens such as Streptococcus pneumoniae, Klebsiella pneumoniae, Acinetobacter baumannii using in silico technology. Hidden Markov Models (HMMER) was used to identify putative anti-bacterial pneumonia AMPs against the identified receptor proteins of Streptococcus pneumoniae, Klebsiella pneumoniae, and Acinetobacter baumannii. The physicochemical parameters of these putative AMPs were computed and their 3-D structures were predicted using I-TASSER. These AMPs were subsequently subjected to docking interaction analysis against the identified bacterial pneumonia pathogen proteins using PATCHDOCK. Results: The in silico results showed 18 antibacterial AMPs which were ranked based on their E values with significant physicochemical parameters in conformity with known experimentally validated AMPs. The AMPs also bound the pneumonia receptors of their respective pathogens sensitively at the extracellular regions. Conclusions: The propensity of these AMPs to bind pneumonia pathogens proteins justifies that they would be potential applicant biomarkers for the recognizable detection of these bacterial pathogens in a point-of-care POC pneumonia diagnostics. The high sensitivity, accuracy, and specificity of the AMPs likewise justify the utilization of HMMER in the design and discovery of AMPs for disease diagnostics and therapeutics. Keywords: Antimicrobial peptides, Bacteria, Databases, Algorithms, Pathogens, Diagnostics, Receptors, Protein and ligands * Correspondence: [email protected] 1Bioinformatics Research Group, Biotechnology Department, University of the Western Cape, Cape Town 7535, South Africa 2Environmental Biotechnology Laboratory, Biotechnology Department, University of the Western Cape, Cape Town 7535, South Africa © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bakare et al. BMC Molecular and Cell Biology (2020) 21:82 Page 2 of 13 Background spectrum activities, low toxicity, and low resistance by mi- Pneumonia disease is an infection of the lung parenchyma crobes. These significant advantages give them huge and it is one of the major causes of critical illness through- popularity and attention as novel antimicrobial agents. out the world [1]. Approximately, 150 million cases occur Previous research has also reported the use of AMPs as every year among children under 5 years of age and the eld- diagnostic agents against p24 of HIV [12] which were sub- erly, resulting in approximately 20 million hospitalizations. sequently validated for point-of-care (POC) use [1]. In this Treatment of the disease is hampered by a lack of sensitive research, a similar effort would be made to use AMPs as diagnosis [2] as biomarkers which hitherto have been iden- biomarkers against pneumonia receptors. tified for its diagnosis, lack specificity because they are im- Apart from this, several in silico tools exist to identify plicated in other diseases such as pulmonary tuberculosis novel AMPs that are fast, cheap, and less-labor intensive and Human Immunodeficiency Virus (HIV). The growing thus speeding up the discoveryprocess.Amongthemisthe problems of diagnosis of this disease and the difficulty of re- Hidden Markov Models (HMMER) software which has sev- sistance to conventional antibiotics, there is growing atten- eral modules to perform optimally using several command tion in the laboratory and pharmacological application of lines. The high sensitivity of the HMMER profiles is due to antimicrobial peptides to detect and treat infections. the combination of the scoring system in the form of E- Five diagnostic biomarkers have been linked to the diag- value. The E-value gives more information about the prob- nosis of pneumonia, namely: C-reactive protein (CRP), Pro- ability of that predicted AMPs to be true positive or false calcitonin (PCT), a Soluble triggering receptor expressed negative AMPs [13, 14]. The appropriate use of the HMME on myeloid cells-1 (STREM-1), CD163, and High Mobility R algorithm enables a more sophisticated search of novel Group Box-1(HMGB-1). CRP and PCT have been proven peptides through scanning of the proteome. useful in diagnosis as they are produced in considerably This research work aimed to generate parameters for high concentration but there is ambiguity in their specificity AMPs that could be used as novel biomarkers for bacterial towards pneumonia because they can be produced in re- pneumonia diagnosis with a view to speeding up accurate sponse to other inflammatory stimuli in the neuron, athero- diagnosis using in-silico technology such as HMMER. This sclerotic plaques, myocytes, and lymphocytes [3]; whilst, is because the discovery of more biomarkers is imperative, the mechanism regulating their syntheses at these sites is using bioinformatics for example, for more accurate diag- not clearly understood [4]. There are other biomarkers that nosis and assurance of functional specificity to ameliorate are currently being studied for their probable link with the aforementioned problems associated with pneumonia pneumonia diagnosis; these include copeptin, cortisol, biomarkers. With this, there is a potential promising per- endotoxin, pro-adrenomedullin, amongst others, yet their spective to reduce the problems of indiscriminate overuse, roles in pneumonia are not understood [3]. toxicity due to the wrong prescription, bacterial resistance, Apart from this, the methods of detection of the bio- scarcity, and the high cost of existing antibiotics. markers implicated in pneumonia disease have been con- stantly advanced, ranging from poor sensitivity of blood Results cultures [5],theinabilityofX-raytoidentifythecausative Retrieval of anti-bacterial AMPs (BAP-AMPs) pathogen [6], overwhelming lack of sensitivity and specifi- In this section, experimentally validated AMPs were re- city of the polymerase chain reaction [7], inability to iden- trieved from various databases where literature mining re- tify only a few bacterial pneumonia pathogens in matrix- vealed that CAMP, APD, and BACTIBASE had 155, 9, and assisted laser desorption or ionization-time of flight [8], to 4 experimentally validated bacterial anti-pneumonia anti- expensive and lack of sensitivity of immunofiltration and microbial peptides (BAP-AMPs) respectively. BAP-AMPs turbidimetric immunoassay [9]. The implication of the use against the pathogens Klebsiella pneumonia totaled 140 of these methods for pneumonia biomarkers identification peptides, Streptococcus pneumoniae totalled 16, and Acine- is the generation of false-negative and false-positive results tobacter baumannii totaled 12 peptides combined from the in patients [6]. It is therefore important to explore other various databases (see Table 1). These experimentally vali- more reliable methods with improved sensitivity and dated anti-pneumonia AMPs were derived from bacteria, accuracy towards pneumonia. arthropods, Mammalia Amphibia, nematode, Pisces, Arach- Furthermore, antimicrobial peptides (AMPs) are part of nida, aves, plants, reptilian, fungi, and viruses with the num- the innate immune systems that shield multicellular organ- bers for each division indicated in Table 1.Thepeptide isms from a diverse spectrum of micro-organisms [10]. total in Table 1 represents
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