Prioritizing drug targets in Clostridium botulinum with a computational systems biology approach

Syed Aun Muhammad, Safia Ahmed, Amjad Ali, Hui Huang, Xiaogang Wu, X. Yang, Anam Naz, Jake Chen

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

A computational and in silico system level framework was developed to identify and prioritize the antibacterial drug targets in Clostridium botulinum (Clb), the causative agent of flaccid paralysis in humans that can be fatal in 5 to 10% of cases. This disease is difficult to control due to the emergence of drug-resistant pathogenic strains and the only available treatment antitoxin which can target the neurotoxin at the extracellular level and cannot reverse the paralysis. This study framework is based on comprehensive systems-scale analysis of genomic sequence homology and phylogenetic relationships among Clostridium, other infectious bacteria, host and human gut flora. First, the entire 2628-annotated genes of this bacterial genome were categorized into essential, non-essential and virulence genes. The results obtained showed that 39% of essential proteins that functionally interact with virulence proteins were identified, which could be a key to new interventions that may kill the bacteria and minimize the host damage caused by the virulence factors. Second, a comprehensive comparative COGs and blast sequence analysis of these proteins and host proteins to minimize the risks of side effects was carried out. This revealed that 47% of a set of C. botulinum proteins were evolutionary related with Homo sapiens proteins to sort out the non-human homologs. Third, orthology analysis with other infectious bacteria to assess broad-spectrum effects was executed and COGs were mostly found in Clostridia, Bacilli (Firmicutes), and in alpha and beta Proteobacteria. Fourth, a comparative phylogenetic analysis was performed with human microbiota to filter out drug targets that may also affect human gut flora. This reduced the list of candidate proteins down to 131. Finally, the role of these putative drug targets in clostridial biological pathways was studied while subcellular localization of these candidate proteins in bacterial cellular system exhibited that 68% of the proteins were located in the cytoplasm, out of which 6% was virulent. Finally, this framework may serve as a general computational strategy for future drug target identification in infectious diseases.

Original languageEnglish
Pages (from-to)24-35
Number of pages12
JournalGenomics
Volume104
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Clostridium botulinum
Systems Biology
Computational Biology
Pharmaceutical Preparations
Proteins
Clostridium
Bacteria
Paralysis
Virulence
Betaproteobacteria
Antitoxins
Alphaproteobacteria
Bacterial Genomes
Bacterial Proteins
Microbiota
Protein Sequence Analysis
Neurotoxins
Virulence Factors
Sequence Homology
Computer Simulation

Keywords

  • Clostridium botulinum
  • Drug targets prioritization
  • In silico analysis
  • Interactome

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

Prioritizing drug targets in Clostridium botulinum with a computational systems biology approach. / Muhammad, Syed Aun; Ahmed, Safia; Ali, Amjad; Huang, Hui; Wu, Xiaogang; Yang, X.; Naz, Anam; Chen, Jake.

In: Genomics, Vol. 104, No. 1, 2014, p. 24-35.

Research output: Contribution to journalArticle

Muhammad, SA, Ahmed, S, Ali, A, Huang, H, Wu, X, Yang, X, Naz, A & Chen, J 2014, 'Prioritizing drug targets in Clostridium botulinum with a computational systems biology approach', Genomics, vol. 104, no. 1, pp. 24-35. https://doi.org/10.1016/j.ygeno.2014.05.002
Muhammad, Syed Aun ; Ahmed, Safia ; Ali, Amjad ; Huang, Hui ; Wu, Xiaogang ; Yang, X. ; Naz, Anam ; Chen, Jake. / Prioritizing drug targets in Clostridium botulinum with a computational systems biology approach. In: Genomics. 2014 ; Vol. 104, No. 1. pp. 24-35.
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