Metabolic Network Analysis-Based Identification of Antimicrobial Drug Targets in Category A Bioterrorism Agents

Abstract

The 2001 anthrax mail attacks in the United States demonstrated the potential threat of bioterrorism, hence driving the need to develop sophisticated treatment and diagnostic protocols to counter biological warfare. Here, by performing flux balance analyses on the fully-annotated metabolic networks of multiple, whole genome-sequenced bacterial strains, we have identified a large number of metabolic enzymes as potential drug targets for each of the three Category A-designated bioterrorism agents including Bacillus anthracis, Francisella tularensis and Yersinia pestis. Nine metabolic enzymes- belonging to the coenzyme A, folate, phosphatidyl-ethanolamine and nucleic acid pathways common to all strains across the three distinct genera were identified as targets. Antimicrobial agents against some of these enzymes are available. Thus, a combination of cross species-specific antibiotics and common antimicrobials against shared targets may represent a useful combinatorial therapeutic approach against all Category A bioterrorism agents.

Metabolic Network Analysis-Based Identification of Antimicrobial Drug Target in Pathogenic Bacteria

“…holartica, F. tularensis mediasatica, and F. tularensis spp. Neither NMN synthetase nor NAD synthetases were identified to be essential in our study (Ahn et al, 2014). F. tularensis (Biovar type A) is highly virulent and occurs predominantly in North America.…”

“…F. tularensis can be grouped into four distinct subspecies; F. tularensis spp. Ahn et al (2014) identified a total of 46 single essential enzymes across the seven species and the majority of them were in the vitamins, cofactors, and cell-wall biosynthesis pathways. holartica, F. tularensis mediasatica, and F. tularensis spp.…”

Systems and synthetic biology perspective of the versatile plant-pathogenic and polysaccharide-producing bacterium Xanthomonas campestris

“…A genome-scale model of E. coli was used to provide the organism with direct biocatalytic routes to 1,4-butanediol [212] and to identify better drug targets or biosynthetic pathways for antibiotics [213][214][215][216].…”

Francisella tularensisas a potential agent of bioterrorism?

“…The F. tularensis metabolic and virulence factors allowing this bacterium to resist the attack by phagocytic cells and adapt to their intracellular niche can be considered potential targets for the development of new therapeutic strategies. Analyzing metabolic networks in category A bioterrorism agents, Ahn et al [23] identified enzymes that could potentially serve as new antimicrobial drug targets, especially those belonging to the biosynthesis pathways of vitamins, cofactors and the bacterial cell wall. Using an integrated in silico/in vitro approach, Chaudhury et al [24] also selected compounds with potential F. tularensis metabolism inhibitory activity, especially by targeting pantetheine-phosphate adenylyltransferase, an enzyme involved in coenzyme A biosynthesis.…”