ArticleACS chemical biology2014
Identification and characterization of an allosteric inhibitory site on dihydropteroate synthase.
Article in ACS chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 38 citations in OpenAlex.
- A virtual screening and molecular dynamics approach in search of novel antibiotic chemotypes.PloS one · 2026Article
- Molecular Dynamics Simulations Demonstrate Reduced Antibiotic Affinity to Mirror Bacterial Targets.Computational and structural biotechnology journal · 2026Article
- Targeting protein-protein interaction interfaces with antiviral N protein inhibitor in SARS-CoV-2.Biophysical journal · 2024Article
- Genotypic Antimicrobial Resistance Profiles of DiarrheagenicInfection and drug resistance · 2024Article
- Modulation of a conformational ensemble by a small molecule that inhibits key protein-protein interactions involved in cell adhesion.Protein science : a publication of the Protein Society · 2023Article
- Molecular mechanism of plasmid-borne resistance to sulfonamide antibiotics.Nature communications · 2023Article
- Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam.Plant communications · 2022Article
- Revitalizing antifolates through understanding mechanisms that govern susceptibility and resistance.MedChemComm · 2019Review
- An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge.MedChemComm · 2018Review
- The Structural and Functional Basis for Recurring Sulfa Drug Resistance Mutations inFrontiers in microbiology · 2018Article
- Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity.Antimicrobial agents and chemotherapy · 2016Review
- Antibacterial Antifolates: From Development through Resistance to the Next Generation.Cold Spring Harbor perspectives in medicine · 2016Review
- Alternative modulation of protein-protein interactions by small molecules.Current opinion in biotechnology · 2015Review
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
The declining effectiveness of current antibiotics due to the emergence of resistant bacterial strains dictates a pressing need for novel classes of antimicrobial therapies, preferably against molecular sites other than those in which resistance mutations have developed. Dihydropteroate synthase (DHPS) catalyzes a crucial step in the bacterial pathway of folic acid synthesis, a pathway that is absent in higher vertebrates. As the target of the sulfonamide class of drugs that were highly effective until resistance mutations arose, DHPS is known to be a valuable bacterial Achilles heel that is being further exploited for antibiotic development. Here, we report the discovery of the first known allosteric inhibitor of DHPS. NMR and crystallographic studies reveal that it engages a previously unknown binding site at the dimer interface. Kinetic data show that this inhibitor does not prevent substrate binding but rather exerts its effect at a later step in the catalytic cycle. Molecular dynamics simulations and quasi-harmonic analyses suggest that the effect of inhibitor binding is transmitted from the dimer interface to the active-site loops that are known to assume an obligatory ordered substructure during catalysis. Together with the kinetics results, these structural and dynamics data suggest an inhibitory mechanism in which binding at the dimer interface impacts loop movements that are required for product release. Our results potentially provide a novel target site for the development of new antibiotics.
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