# Site-Divergent Oxidations within Venerable Macrolide Antibiotic Scaffolds Unveil Compounds with Broad Spectrum and Anti-MRSA Activities

## TL;DR

Scientists developed a new method to modify macrolide antibiotics, creating compounds that work against a wide range of bacteria, including drug-resistant strains.

## Contribution

A new azaadamantyl oxoammonium catalyst enables site-selective oxidation of macrolides, generating broad-spectrum and anti-MRSA derivatives.

## Key findings

- Oxidized macrolide derivatives retain activity against a broad range of pathogens.
- Three compounds show antibiotic activity against CA-MRSA and MRSA(mph(C)), unlike their clinical analogs.
- The oxidation method allows selective modification without full de novo synthesis.

## Abstract

The synthesis of bioactive compounds with differential,
and ideally
enhanced, activities presents persistent and growing challenges for
the field of organic synthesis. By leveraging Nature’s ability
to build complex, stereochemically rich, and biologically active molecular
scaffolds, site-selective modification of natural products can deliver
analogs without the need for lengthy de novo syntheses.
Yet, achieving selective reactivity at a single desired position is
complicated by the presence of multiple iterations of similar reactive
functional groups, thus precluding widespread adoption of catalyst-controlled
site-selective modification. Herein we describe the development of
complementary systems for the oxidation of secondary alcohols on erythromycin
A, clarithromycin, and azithromycin using a newly designed azaadamantyl
oxoammonium catalyst, wherein different hydroxyl groups show disparate
reactivities under the same conditions. The application of this methodology
has enabled the generation of a suite of oxidized macrolide antibiotics
and derivatives that take advantage of the newly installed carbonyls.
Antimicrobial activity testing revealed that multiple compounds retain
activity against a broad range of pathogens consistent with erythromycin
A coverage. Additionally, three of the compounds reported herein display
antibiotic activity against CA-MRSA and MRSA­(mph(C)),
for which the clinical analogs erythromycin A, clarithromycin, and
azithromycin exhibit no activity at tested concentrations.