Track topics on Twitter Track topics that are important to you
The enoyl-acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti-staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically-relevant activity against multidrug-resistant S. aureus . By combining X-ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti-staphylococcal drug development.
This article was published in the following journal.
Name: Angewandte Chemie (International ed. in English)
The 3-ketoacyl-ACP synthase (KAS) III proteins are one of the most abundant enzymes in nature, as they are involved in the biosynthesis of fatty acids and natural products. KAS III enzymes catalyse a ...
The essentiality of fatty acid synthesis (FASII) products in the human pathogen Staphylococcus aureus is the underlying rationale for FASII-targeted antimicrobial drug design. Reports of anti-FASII ef...
Enormous fuel consumption and growing environmental concerns have been spurring development of renewable biofuels. Among various biofuels, fatty acid-derived biohydrocarbons are ideal alternatives to ...
The heterologous biosynthesis of complex natural products has enabled access to polyketide, nonribosomal peptide, isoprenoid, and other compounds with wide-spanning societal value. Though several surr...
Three homologous oxygenated elansolid-type of polyketide spanned macrolides were isolated from a heterotrophic marine bacterium, Bacillus amyloliquefaciens MTCC 12716 associated with an intertidal red...
A randomized, clinical trial to provide the first comprehensive investigation of the role of fatty acid desaturate (FADS) genetic determinants on PUFA biosynthesis and metabolism as well a...
The purpose of this study is to learn more about what causes insulin resistance. It has been suggested that proper breakdown of fat into energy (oxidation) in the body is important to all...
This is a Phase Ib, randomized double-blind, placebo-controlled multiple-ascending dose study to investigate the safety, tolerability, and pharmacokinetics of multiple doses of DSTA4637S w...
This study investigates the therapeutic efficacy and safety of omega-3 fatty acids rich in eicosapentaenoic acid / docosahexaenoic acid in pediatric depression in a nine months double-blin...
This study is being done to detect the metabolic changes that Omega 3 fatty acid treatment has on the brain and to find out whether magnetic resonance spectroscopy (MRS) scan can detect me...
A doubly unsaturated fatty acid, occurring widely in plant glycosides. It is an essential fatty acid in mammalian nutrition and is used in the biosynthesis of prostaglandins and cell membranes. (From Stedman, 26th ed)
A fatty acid coenzyme derivative which plays a key role in fatty acid oxidation and biosynthesis.
A species of STAPHYLOCOCCUS similar to STAPHYLOCOCCUS HAEMOLYTICUS, but containing different esterases. The subspecies Staphylococcus hominis novobiosepticus is highly virulent and novobiocin resistant.
S-Acyl coenzyme A. Fatty acid coenzyme A derivatives that are involved in the biosynthesis and oxidation of fatty acids as well as in ceramide formation.
An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...