Wang resin catalysed sonochemical synthesis of pyrazolo[4,3-d]pyrimidinones and 2,3-dihydroquinazolin-4(1H)-ones: Identification of chorismate mutase inhibitors having effects on Mycobacterium tuberculosis cell viability

Shukla, Sharda; Rao, R. Nishanth; Bhuktar, Harshavardhan; Edwin, Rebecca Kristina; Trinath, Jamma; Medishetti, Raghavender; Banerjee, Sharmistha; Giliyaru, Varadaraj Bhat; Shenoy, Gautham G.; Oruganti, Srinivas; Misra, Parimal; Pal, Manojit

doi:10.1016/j.bioorg.2023.106452

Cited by 9 publications

(4 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phe biosynthesis also requires conversion of chorismate to prephenate by chorismate mutase [44]. Inhibitors of M. tuberculosis chorismate mutase have been identified, but most of these compounds had high minimal inhibitory concentrations (MICs), suggesting that they have low whole cell permeability [51-53]. Our data suggest that M. tuberculosis can import Phe, since growth of the pheA ::Tn mutant in vitro was restored by amino acid supplementation.…”

Section: Discussionmentioning

confidence: 88%

Mycobacterium tuberculosisrequires conditionally essential metabolic pathways for infection

Block,

Wiegert,

Namugenyi

et al. 2023

Preprint

View full text Add to dashboard Cite

New drugs are needed to shorten and simplify treatment of tuberculosis caused by Mycobacterium tuberculosis. Metabolic pathways that M. tuberculosis requires for growth or survival during infection represent potential targets for anti-tubercular drug development. Genes and metabolic pathways essential for M. tuberculosis growth in standard laboratory culture conditions have been defined by genome-wide genetic screens. However, whether M. tuberculosis requires these essential genes during infection has not been comprehensively explored because mutant strains cannot be generated using standard methods. Here we show that M. tuberculosis requires functional phenylalanine (Phe) and de novo purine and thiamine biosynthetic pathways for mammalian infection. We used a defined collection of M. tuberculosis transposon (Tn) mutants in essential genes, which we generated using a custom nutrient-rich medium, and transposon sequencing (Tn-seq) to identify multiple central metabolic pathways required for fitness in a mouse infection model. We confirmed by individual retesting and complementation that mutations in pheA (Phe biosynthesis) or purF (purine and thiamine biosynthesis) cause death of M. tuberculosis in the absence of nutrient supplementation in vitro and strong attenuation in infected mice. Our findings show that Tn-seq with defined Tn mutant pools can be used to identify M. tuberculosis genes required during mouse lung infection. Our results also demonstrate that M. tuberculosis requires Phe and purine/thiamine biosynthesis for survival in the host, implicating these metabolic pathways as prime targets for the development of new antibiotics to combat tuberculosis.

show abstract

Section: Discussionmentioning

confidence: 88%

Mycobacterium tuberculosisrequires conditionally essential metabolic pathways for infection

Block,

Wiegert,

Namugenyi

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…tuberculosis chorismate mutase, which is also required for Phe synthesis [ 45 ], have been identified. However, most of these compounds had high minimal inhibitory concentrations (MICs), suggesting they have low whole cell permeability [ 58 – 60 ]. Since M .…”

Section: Discussionmentioning

confidence: 99%

“…Inhibitors of M. tuberculosis chorismate mutase, which is also required for Phe synthesis [45], have been identified. However, most of these compounds had high minimal inhibitory concentrations (MICs), suggesting they have low whole cell permeability [58][59][60]. Since M. tuberculosis imports Phe, it may be possible to design PheA or chorismate mutase inhibitors with improved permeability properties.…”

Section: Plos Pathogensmentioning

confidence: 99%

Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection

Block,

Wiegert,

Namugenyi

et al. 2024

PLoS Pathog

View full text Add to dashboard Cite

New drugs are needed to shorten and simplify treatment of tuberculosis caused by Mycobacterium tuberculosis. Metabolic pathways that M. tuberculosis requires for growth or survival during infection represent potential targets for anti-tubercular drug development. Genes and metabolic pathways essential for M. tuberculosis growth in standard laboratory culture conditions have been defined by genome-wide genetic screens. However, whether M. tuberculosis requires these essential genes during infection has not been comprehensively explored because mutant strains cannot be generated using standard methods. Here we show that M. tuberculosis requires the phenylalanine (Phe) and de novo purine and thiamine biosynthetic pathways for mammalian infection. We used a defined collection of M. tuberculosis transposon (Tn) mutants in essential genes, which we generated using a custom nutrient-rich medium, and transposon sequencing (Tn-seq) to identify multiple central metabolic pathways required for fitness in a mouse infection model. We confirmed by individual retesting and complementation that mutations in pheA (Phe biosynthesis) or purF (purine and thiamine biosynthesis) cause death of M. tuberculosis in the absence of nutrient supplementation in vitro and strong attenuation in infected mice. Our findings show that Tn-seq with defined Tn mutant pools can be used to identify M. tuberculosis genes required during mouse lung infection. Our results also demonstrate that M. tuberculosis requires Phe and purine/thiamine biosynthesis for survival in the host, implicating these metabolic pathways as prime targets for the development of new antibiotics to combat tuberculosis.

show abstract

“…The last two steps of the shikimate pathway are catalyzed by 5-enolpyruvylshikimate-3-phosphate synthase (EPSP) and chorismate mutase. Even though genetic studies have assessed their vulnerability as drug targets and crystal structures could aid in the design of structure-based inhibitors [ 28 , 29 ], to date, the development of inhibitors is still in its infancy [ 30 , 31 ].…”

Section: Inhibitors Of Amino Acid Biosynthesismentioning

confidence: 99%

Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

Guida,

Tammaro,

Quaranta

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

According to the latest World Health Organization (WHO) report, an estimated 10.6 million people were diagnosed with tuberculosis (TB) in 2022, and 1.30 million died. A major concern is the emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains, fueled by the length of anti-TB treatment and HIV comorbidity. Innovative anti-TB agents acting with new modes of action are the only solution to counteract the spread of resistant infections. To escape starvation and survive inside macrophages, Mtb has evolved to become independent of the host by synthesizing its own amino acids. Therefore, targeting amino acid biosynthesis could subvert the ability of the mycobacterium to evade the host immune system, providing innovative avenues for drug discovery. The aim of this review is to give an overview of the most recent progress in the discovery of amino acid biosynthesis inhibitors. Among the hits discovered over the past five years, tryptophan (Trp) inhibitors stand out as the most advanced and have significantly contributed to demonstrating the feasibility of this approach for future TB drug discovery. Future efforts should be directed at prioritizing the chemical optimization of these hits to enrich the TB drug pipeline with high-quality leads.

show abstract

Wang resin catalysed sonochemical synthesis of pyrazolo[4,3-d]pyrimidinones and 2,3-dihydroquinazolin-4(1H)-ones: Identification of chorismate mutase inhibitors having effects on Mycobacterium tuberculosis cell viability

Cited by 9 publications

References 44 publications

Mycobacterium tuberculosisrequires conditionally essential metabolic pathways for infection

Mycobacterium tuberculosisrequires conditionally essential metabolic pathways for infection

Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection

Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

Contact Info

Product

Resources

About