The tryptophan biosynthetic pathway is essential forMycobacterium tuberculosisto cause disease

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is the most significant cause of death from a single infectious agent worldwide. Antibiotic-resistant strains of M. tuberculosis represent a threat to effective treatment, and the long duration, toxicity and complexity of current chemotherapy for antibiotic-resistant disease presents a need for new therapeutic approaches with novel modes of action. M. tuberculosis is an intracellular pathogen that must survive phagocytosis by macrophages, dendritic cells or neutrophils to establish an infection. The tryptophan biosynthetic pathway is required for bacterial survival in the phagosome, presenting a target for new classes of antitubercular compound. The enzymes responsible for the six catalytic steps that produce tryptophan from chorismate have all been characterised in M. tuberculosis, and inhibitors have been described for some of the steps. The innate immune system depletes cellular tryptophan in response to infection in order to inhibit microbial growth, and this effect is likely to be important for the efficacy of tryptophan biosynthesis inhibitors as new antibiotics. Allosteric inhibitors of both the first and final enzymes in the pathway have proven effective, including by a metabolite produced by the gut biota, raising the intriguing possibility that the modulation of tryptophan biosynthesis may be a natural inter-bacterial competition strategy.

Revealing the Metabolic Alterations during Biofilm Development of Burkholderia cenocepacia Based on Genome-Scale Metabolic Modeling

“…In this manner, Zhang et al showed that the absence of exogenous tryptophan caused an immediate killing on auxotrophic mycobacterium species, which is consistent with our findings [23]. Since tryptophan is not synthesized by human cells, biosynthetic pathways of this amino acid provide excellent targets for the discovery of new antimicrobial agents [24].…”

Indole‐3‐Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target

“…Auxotrophic strains of M. tuberculosis were used to demonstrate that tryptophan biosynthesis is essential for establishing infection in the host. [47,48] Sassetti and co-workers used inactivation by transposon mutagenesis to show that the gene that encodes MtIGPS is essential for the growth of the pathogen in vitro. [16] Therefore, there is an interest in identifying inhibitors of enzymes in the tryptophan biosynthesis pathway that could be tested against the pathogen.…”

Discovery of antimicrobial agent targeting tryptophan synthase

“…One critical pathway in microorganisms is the Ltryptophan (L-Trp) biosynthesis. 6,7 In bacteria, yeast, molds, and plants, the tryptophan operon encodes for enzymes involved in the metabolism of this amino acid. Auxotrophic mutants of pathogenic bacteria with defects in L-Trp biosynthesis lose virulence within a host organism.…”