Synthesis, Stereochemical Confirmation, and Derivatization of 12(S),16ϵ‐Dihydroxycleroda‐3,13‐dien‐15,16‐olide, a Clerodane Diterpene That Sensitizes Methicillin‐Resistant Staphylococcus aureus to β‐Lactam Antibiotics

Abstract

Over the past decades, antibiotic resistance has grown to a point where orthogonal approaches to combating infections caused by resistant bacteria are needed. One such approach is the development of nonmicrobicidal small molecules that potentiate the activity of conventional antibiotics, termed adjuvants. The diterpene natural product 12(S),16ɛ-dihydroxycleroda-3,13-dien-15,16-olide, which we refer to as (À )-LZ-2112, is known to synergize with oxacillin against methicillinresistant Staphylococcus aureus (MRSA). To explore this activity, (À )-LZ-2112 was synthesized and the structure confirmed through X-ray analysis. Preliminary structure-activity relationship studies following the synthesis of several analogs identified key structural elements responsible for activity and indicate that scaffold simplification is possible. A preliminary mode of action study suggests mecA plays a role in the adjuvant activity of (À )-LZ-2112.

β-Lactamase Suppression as a Strategy to Target Methicillin-Resistant Staphylococcus aureus: Proof of Concept

“…This is understandable, as these are only early hits, and will require significant optimization. Our goal is only to reveal the substantially different mechanism of penicillin G enhancers (see details below) in comparison with contemporary − , literature.…”

Multicomponent Selective Thioetherification of KSAc: Easy Access to Symmetrical/Unsymmetrical 4‐Alkylthio‐3‐halo‐2(5H)‐furanones

“…The 2(5H)-furanone compounds bearing an α,β-unsaturated lactone unit have attracted great attention from chemists in many fields, such as organic synthesis, [24,25] drug design, [26,27] and natural product synthesis [28,29] due to their high antiviral, [30] antitumor [31] and anti-HIV biological activities, [32] making the chemical researches of 2(5H)-furanone more active. [33] Among them, the thioetherified 2(5H)-furanone is a kind of potential drug molecule with good anti-cancer activity as Li's group reported before.…”