Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

Abstract

Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

Keywords: antibiotics; cyclization; heterocycles; medicinal chemistry; natural products.

Figure 1

4-Oxazolidinone-containing natural products and related antibiotics. a) Two families of 4-oxazolidinone natural products isolated to date; b) synthetic 2-oxazolidinones developed for the treatment of Gram-positive bacterial infections; c) a one-pot synthetic strategy to synthesize the 4-oxazolidinone core of lipoxazolidinone A.

Figure 2

4-Oxazolidinone method development and synthesis of lipoxazolidinone A. a) initial reaction development for the preparation of 4-oxazolidinones; b) optimized one-pot protocol; c) synthesis of ketene precursor and subsequent conversion to lipoxazolidinone A.

Figure 3

Structure–activity profile of lipoxazolidinone A (1). a) Key structural modifications were performed around the molecule to probe the role of various changes on antimicrobial activity; b) initial evaluation of antimicrobial activity against two S. aureus strains with red highlighting compounds with significant activity or structural modifications. ¹ ATCC 29213; ² ATCC 33591.

Figure 4

Serial passage resistance studies of 29 and ofloxacin on S. aureus ATCC 29213. Resistant mutants were generated for both ofloxacin and 29 through the daily sequential passage of the bacterial with a range of concentrations of antibiotic.

Figure 5

Macromolecular synthesis assay. Radiolabeled precursors (color coded by biosynthetic pathway) were employed with ascending concentrations of 29 to measure the relative impact on macromolecular synthesis pathways. Control antibiotics shown at right.