Subtractive Genomics Approaches: Towards Anti- Bacterial Drug Discovery
Pp. 144-158 (15)
Fatima Shahid, Muhammad Shehroz, Tahreem Zaheer and Amjad Ali
Abstract
Pathogenic bacteria are evolving at a much faster rate and have the ability to
acquire new antibacterial resistance patterns. The most common pathogenic bacteria
are now becoming increasingly resistant to available antibiotics. The CDC has
suggested to find alternative therapeutics to combat the growing antimicrobial
resistance. Thanks to technological development in sequencing platforms and
sophisticated bioinformatics pipelines, it now easier to analyze large-scale genomic
data and propose alternative and novel treatment options. Subtractive genomics is one
such approach that mines whole genomic DNA for identification of potential drug
target(s). This strategy employs various computational filters using databases and
online servers to screen and prioritize certain candidate proteins. Each filter analyzes
the whole proteome of bacteria under study in a step-wise manner. Initially, strainspecific
paralogous and host-specific homologous sequences are subtracted from the
bacterial proteome to remove duplicates and prevent cytotoxicity and autoimmunity
related challenges. The sorted proteome is further refined to identify essential genes
involved in crucial metabolic pathways of the pathogen and thus can be used as targets
for treatment interventions. Functional annotation is carried out to elucidate the
involvement of these proteins in important cellular processes, metabolic pathway, and
subcellular location analyses are carried out for finding the probable cellular location of
the candidate proteins in the cell. Proteins with certain physicochemical properties like
favorable molecular weight, hydrophobicity, and pI are rendered fine drug targets, thus
filter. Importantly, the scrutinized proteins are screened against FDA approved
DrugBank to identify their druggability potential. Finally, molecular docking analyses
of the novel druggable targets with already present drugs are carried out. Only then, the
prioritized candidate proteins can prove to be promising candidates for novel drug
design and development.
Keywords:
Cytoplasmic proteins, Drug targets, Membrane proteins, Metabolic
pathways, Proteome, Subtractive proteomics.
Affiliation:
Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
