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.
Michael J ZeilerGina M ConnorsGreg M DurlingAllen G OliverLewis MarquezRoberta J MelanderCassandra L QuaveRoberta J MelanderPublished in: Angewandte Chemie (International ed. in English) (2022)
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 non-microbicidal small molecules that potentiate the activity of conventional antibiotics, termed adjuvants. The diterpene natural product 12(S),16ϵ-dihydroxycleroda-3,13-dien-15,16-olide, which we refer to as (-)-LZ-2112, is known to synergize with oxacillin against methicillin-resistant Staphylococcus aureus (MRSA). To explore this activity, (-)-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 (-)-LZ-2112.
Keyphrases
- methicillin resistant staphylococcus aureus
- staphylococcus aureus
- early stage
- ms ms
- computed tomography
- structure activity relationship
- liquid chromatography tandem mass spectrometry
- multidrug resistant
- signaling pathway
- gram negative
- endoplasmic reticulum stress
- induced apoptosis
- dual energy
- data analysis
- solid phase extraction