ArticleScientific reports2016
Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 38 citations in OpenAlex.
- Reference-based chemical-genetic interaction profiling to elucidate small molecule mechanism of action in Mycobacterium tuberculosis.Nature communications · 2025Article
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- Modular synthesis of functional libraries by accelerated SuFEx click chemistry.Chemical science · 2024Article
- Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection.PLoS pathogens · 2024Article
- Small Schiff Base Molecules-A Possible Strategy to Combat Biofilm-Related Infections.Antibiotics (Basel, Switzerland) · 2024Review
- Design, spectral, molecular modeling, antimitotic, analytical and mechanism studies of phenyl isothiocyanate Girard's T derived metal complexes.BMC chemistry · 2023Article
- A combination screening to identify enhancers of para-aminosalicylic acid against Mycobacterium tuberculosis.Scientific reports · 2022Article
- Metabolic bifunctionality of Rv0812 couples folate and peptidoglycan biosynthesis in Mycobacterium tuberculosis.The Journal of experimental medicine · 2021Article
- The Power of Chemists Is in What They Can Learn, Not What They Already Know.Chembiochem : a European journal of chemical biology · 2021Article
- Mutations of folC cause increased susceptibility to sulfamethoxazole in Mycobacterium tuberculosis.Scientific reports · 2021Article
- Genomewide Assessment of Mycobacterium tuberculosis Conditionally Essential Metabolic Pathways.mSystems · 2019Article
- Revitalizing antifolates through understanding mechanisms that govern susceptibility and resistance.MedChemComm · 2019Review
- Vitamin Biosynthesis as an Antifungal Target.Journal of fungi (Basel, Switzerland) · 2018Review
- Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole.Nature communications · 2018Article
- Synthesis, Antimicrobial and Antioxidant Activity of Pyrazole Based Sulfonamide Derivatives.Indian journal of microbiology · 2018Article
- Methionine AntagonizesFrontiers in cellular and infection microbiology · 2018Article
- Deletion ofAntimicrobial agents and chemotherapy · 2017Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents.
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