RESUMO
Bacteria continue to evade existing antibiotics by acquiring resistance by various mechanisms, leading to loss of antibiotic effectiveness. To avoid an epidemic from infections of incurable drug-resistant bacteria, new antibiotics with new modes of action are desperately needed. Using a genome-wide mechanism of action-guided whole cell screening approach based on antisense Staphylococcus aureus fitness test technology, we report herein the discovery of altersolanol P (1), a new tetrahydroanthraquinone from an unknown fungus from the Hypocreales isolated from forest litter collected in Puerto Rico. The structure was elucidated by high-resolution mass spectrometry and 2D NMR spectroscopy. Relative stereochemistry was established by NOESY correlations, and absolute configuration was deduced by the application of MPA ester-based methodology. Observed (1)H and (13)C NMR shifts were well aligned with the corresponding chemical shifts predicted by DFT calculations. Altersolanol P exhibited Gram-positive antibacterial activity (MIC range 1-8 µg/mL) and inhibited the growth of Gram-negative Haemophilus influenzae (MIC 2 µg/mL). The isolation, structure elucidation, and antibacterial activity of altersolanol P are described.
Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Hypocreales/química , Staphylococcus aureus/efeitos dos fármacos , Antraquinonas/química , Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Porto RicoRESUMO
Drug-resistant bacteria continue to make many existing antibiotic classes ineffective. In order to avoid a future epidemic from drug-resistant bacterial infections, new antibiotics with new modes of action are needed. In an antibiotic screening program for new drug leads with new modes of action using antisense Staphylococcus aureus Fitness Test screening, we discovered a new tetramic acid, methiosetin, from a tropical sooty mold, Capnodium sp. The fungus also produced epicorazine A, a known antibiotic. The structure and relative configuration of methiosetin was elucidated by 2D NMR and ESIMS techniques. Methiosetin and epicorazine A showed weak to modest antibacterial activity against S. aureus and Haemophilus influenzae. The isolation, structure elucidation, and antibacterial activity of both compounds are described.
Assuntos
Antibacterianos/isolamento & purificação , Ascomicetos/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Guatemala , Haemophilus influenzae/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/isolamento & purificação , Piperazinas/farmacologia , Pirrolidinonas/químicaRESUMO
Bacterial resistance to existing antibiotics continues to grow, necessitating the discovery of new compounds of this type. Antisense-based whole-cell target-based screening is a new and highly sensitive antibiotic discovery approach that has led to a number of new natural product antibiotics. Screening with a rpsD-sensitized strain led to the discovery of a number of natural product polyketides from Streptomyces lucensis. Complete workup of the fermentation extract of this strain allowed for the isolation of seven new compounds, lucensimycins A-G (1-3, 4a, 5-7), with varying degrees of antibacterial activities. Lucensimycin E (5) exhibited the best activity and showed MIC values of 32 microg/mL against Staphylococcus aureus and 8 microg/mL against Streptococcus pneumoniae. The isolation, structure elucidation, and antibacterial activities of four new members, lucensimycins D-G, are described. Lucensimycins D (4a) and E (5) are N-acetyl-l-cysteine adducts of lucensimycin A (1). Semisynthesis of lucensimycins D and E from lucensimycin A has also been described. Lucensimycins F and G are myo-inositolyl-alpha-2-amino-2-deoxy-l-idosyl amide derivatives of lucensimycins D and E, respectively. The relative configuration of these compounds was determined, in part, by molecular dynamics simulations.
Assuntos
Antibacterianos , DNA Bacteriano/genética , Compostos de Espiro , Streptomyces/química , Streptomyces/genética , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , DNA Antissenso/genética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Índias OcidentaisRESUMO
Two new macrolactams, 6-desmethyl-N-methylfluvirucin A1 (1) and N-methylfluvirucin A1 (2), have been isolated from the acetone extract of Nonomuraea turkmeniaca MA7364. These compounds were isolated by bioassay-guided fractionation as part of our search for new anthelmintics. The structures of these compounds were elucidated by comparison of their NMR and MS data to those of previously reported fluvirucins and confirmed by 2D NMR. Compound 1 exhibited in vitro activity (EC(90) 15 +/- 5 microg/mL) against Haemonchus contortus larvae, whereas compound 2, while a bit less active in vitro (EC(90) 29 +/- 8 microg/mL), showed modest in vivo activity against a surrogate organism, Heligmosomoides polygyrus in mice, at 50 mg/kg.
Assuntos
Actinomycetales/química , Anti-Helmínticos , Haemonchus/efeitos dos fármacos , Lactamas , Plantas Medicinais/química , Animais , Anti-Helmínticos/química , Anti-Helmínticos/isolamento & purificação , Anti-Helmínticos/farmacologia , Lactamas/química , Lactamas/isolamento & purificação , Lactamas/farmacologia , Larva/efeitos dos fármacos , México , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
Tat is a small HIV protein essential for both viral replication and the progression of HIV disease. In our efforts to discover Tat inhibitors from natural product screening of microbial fermentation extracts, we discovered durhamycin A (1) as a potent inhibitor (IC(50) = 4.8 nM) of Tat transactivation. Detailed NMR and MS/MS studies were utilized to elucidate the structure of 1 as a new member of the aureolic acid family of antibiotics. It consists of tetrasaccharide and disaccharide moieties attached to the aglycone, which is hitherto unknown in the aureolic acid family. Three other novel analogues, durhamycin B (2), compound (3), and the aglycone (4), were also discovered or chemically prepared that were less potent than durhamycin A.