The Fatty Acid Synthase Inhibitor Platensimycin Improves Insulin Resistance without Inducing Liver Steatosis in Mice and Monkeys

<div><p>Objectives</p><p>Platensimycin (PTM) is a natural antibiotic produced by <i>Streptomyces platensis</i> that selectively inhibits bacterial and mammalian fatty acid synthase (FAS) without affecting synthesis of other lipids. Recently, we reported that oral administration of PTM in mouse models (<i>db/db</i> and <i>db/+</i>) with high <i>de novo</i> lipogenesis (DNL) tone inhibited DNL and enhanced glucose oxidation, which in turn led to net reduction of liver triglycerides (TG), reduced ambient glucose, and improved insulin sensitivity. The present study was conducted to explore translatability and the therapeutic potential of FAS inhibition for the treatment of diabetes in humans.</p><p>Methods</p><p>We tested PTM in animal models with different DNL tones, i.e. intrinsic synthesis rates, which vary among species and are regulated by nutritional and disease states, and confirmed glucose-lowering efficacy of PTM in lean NHPs with quantitation of liver lipid by MRS imaging. To understand the direct effect of PTM on liver metabolism, we performed <i>ex vivo</i> liver perfusion study to compare FAS inhibitor and carnitine palmitoyltransferase 1 (CPT1) inhibitor.</p><p>Results</p><p>The efficacy of PTM is generally reproduced in preclinical models with DNL tones comparable to humans, including lean and established diet-induced obese (eDIO) mice as well as non-human primates (NHPs). Similar effects of PTM on DNL reduction were observed in lean and type 2 diabetic rhesus and lean cynomolgus monkeys after acute and chronic treatment of PTM. Mechanistically, PTM lowers plasma glucose in part by enhancing hepatic glucose uptake and glycolysis. Teglicar, a CPT1 inhibitor, has similar effects on glucose uptake and glycolysis. In sharp contrast, Teglicar but not PTM significantly increased hepatic TG production, thus caused liver steatosis in eDIO mice.</p><p>Conclusions</p><p>These findings demonstrate unique properties of PTM and provide proof-of-concept of FAS inhibition having potential utility for the treatment of diabetes and related metabolic disorders.</p></div

Correction: The Fatty Acid Synthase Inhibitor Platensimycin Improves Insulin Resistance without Inducing Liver Steatosis in Mice and Monkeys.

[This corrects the article DOI: 10.1371/journal.pone.0164133.]

Isolation, Structure Elucidation, and Antibacterial Activity of Methiosetin, a Tetramic Acid from a Tropical Sooty Mold (<i>Capnodium</i> sp.)

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 <i>Staphylococcus aureus</i> Fitness Test screening, we discovered a new tetramic acid, methiosetin, from a tropical sooty mold, <i>Capnodium</i> 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 <i>S. aureus</i> and <i>Haemophilus influenzae</i>. The isolation, structure elucidation, and antibacterial activity of both compounds are described

Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties

Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Platencin shows potent in vivo efficacy without any observed toxicity. It targets two essential proteins, β-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC(50) values of 1.95 and 3.91 μg/ml, respectively, whereas platensimycin targets only FabF (IC(50) = 0.13 μg/ml) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by using this antisense differential sensitivity whole-cell screening paradigm