A platform for the discovery of new macrolide antibiotics

Abstract

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

“…The results thus far demonstrate structure activity relationships that can likely be built upon to achieve these goals, and a recent report on the fully synthetic assembly of 300 new macrolide candidates suggests further candidates for screening (42).…”

A Bright Future for Antibiotics?

“…Popular among these efforts are attempts to create libraries of potential drugs by mining underexplored microbial niches or designing chemical probes for improving known molecular scaffolds. Hence, most clinically used antibiotics originate from a small set of molecular scaffolds (88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99).…”

“…An interesting example is the fully synthetic platform for the discovery and manufacture of new macrolide antibiotics by the convergent assembly of simple chemical building blocks, which has already yielded more than 300 new macrolide antibiotic candidates, some of which showed antibiotic activity even in strains resistant to commonly used macrolides (90). Likewise, extensive efforts are being made for establishing molecular genetic tools for manipulation of biosynthetic pathways that are expected to yield state-of-the-art targeted methods for understanding and manipulating antibiotic binding sites (91)(92) and for exploiting different segments, such as polyketides in conjugates with peptides (e.g., bactobolin) (49).…”

Fighting bacterial resistance: approaches, challenges, and opportunities in the search for new antibiotics.Part 1. Antibiotics used in clinical practice: mechanisms of action and the development of bacterial resistance

“…The latter has a significantly improved affinity to both the native and mutant 50S ribosome subunits, although the new mutations that lead to this antibiotic resistance have already been reported [81]. Summary of practical methods of synthesis of new macrolide antibiotics is presented by Seiple et al [82].…”