Novel Target Exploration from Hypothetical Proteins of Klebsiella pneumoniae MGH 78578 Reveals a Protein Involved in Host-Pathogen Interaction

Abstract

The opportunistic pathogen Klebsiella pneumoniae is a causative agent of several hospital-acquired infections. It has become resistant to a wide range of currently available antibiotics, leading to high mortality rates among patients; this has further led to a demand for novel therapeutic intervention to treat such infections. Using a series of in silico analyses, the present study aims to explore novel drug/vaccine candidates from the hypothetical proteins of K. pneumoniae. A total of 540 proteins were found to be hypothetical in this organism. Analysis of these 540 hypothetical proteins revealed 30 pathogen-specific proteins essential for pathogen survival. A motifs/domain family analysis, similarity search against known proteins, gene ontology, and protein-protein interaction analysis of the shortlisted 30 proteins led to functional assignment for 17 proteins. They were mainly cataloged as enzymes, lipoproteins, stress-induced proteins, transporters, and other proteins (viz., two-component proteins, skeletal proteins and toxins). Among the annotated proteins, 16 proteins, located in the cytoplasm, periplasm, and inner membrane, were considered as potential drug targets, and one extracellular protein was considered as a vaccine candidate. A druggability analysis indicated that the identified 17 drug/vaccine candidates were "novel". Furthermore, a host-pathogen interaction analysis of these identified target candidates revealed a betaine/carnitine/choline transporters (BCCT) family protein showing interactions with five host proteins. Structure prediction and validation were carried out for this protein, which could aid in structure-based inhibitor design.

Gut Microbiota Composition and Its Metabolites in Different Stages of Chronic Kidney Disease

“…K. pneumonia has been demonstrated to be capable of encoding the 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase involved in the production of S-adenosylhomocysteine [49]. In addition, the presence of L-Carnitine was documented to facilitate the interaction between host cells and K. pneumonia, which may interfere with the integrity or barrier function of the intestinal wall [50]. These results suggested that the interplay between K. pneumonia and S-Adenosylhomocysteine may function as a putative mechanism toward the deterioration of CKD.…”

Integrated bioinformatics based subtractive genomics approach to decipher the therapeutic function of hypothetical proteins from Salmonella typhi XDR H-58 strain

“…The functional annotation and sub-cellular localization identification of these hypothetical proteins are of major importance that provides insights into the molecular function and to understand their interactions with the drug molecules and with other proteins inside the cell. This information is useful for the identification of new drugs against the disease (Pranavathiyani et al 2020 ). Here, the main goal of the current study was to determine the function of the hypothetical proteins and eventually to prioritize potential drug targets among them against S. typhi XDR H58 (Ali et al 2016 ; Sivashankari and Shanmughavel 2006 ).…”

“…During genome analysis, these hypothetical proteins are predicted by various software as a large open reading frame without a characterized homologue in the protein database. It returns "hypothetical protein" as an annotation remark (da Costa et al 2018 ; Pranavathiyani et al 2020 ). It is vital to understand the function of hypothetical proteins as many of them might be associated with the disease conditions.…”

A Molecular Interaction Map of Klebsiella pneumoniae and Its Human Host Reveals Potential Mechanisms of Host Cell Subversion

“…There are mainly four types of virulence factors in K. pneumoniae : (i) capsule ( Struve and Krogfelt, 2003 ; Schembri et al, 2005 ; Evrard et al, 2010 ; Rendueles, 2020 ), (ii) fimbriae ( Murphy et al, 2013 ; Lin et al, 2017 ), (iii) lipopolysaccharides ( Kamaladevi and Balamurugan, 2016 ), and (iv) siderophores ( Holden et al, 2016 , 2018 ; Zhang et al, 2017 ) that have been well studied and are important for virulence in infection models. However, there are several genes in the K. pneumoniae genome that remain poorly characterized and might have potential roles in virulence ( Pranavathiyani et al, 2020 ). A previous study has identified some of the in vivo fitness genes in K. pneumoniae which are required by this pathogen to survive and adapt to the host environment ( Bachman et al, 2015 ).…”