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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. A practical, fully synthetic route to macrolide antibiotics via the convergent assembly of simple chemical building blocks is described; more than 300 new macrolide antibiotic candidates have been synthesized using this approach, a number of which are active against bacterial strains that are resistant to currently used antibiotics. Towards a new breed of macrolide antibiotics Most antibacterial drugs used today are the products of semisynthesis, or partial chemical synthesis, based on the modification of natural fermentation products. Now, many of these antibiotics have been rendered ineffective by the spread of bacterial resistance. Macrolide antibiotics — macrocyclic lactones produced in streptomycetes — have been one of the most productive groups and this paper describes a practical synthetic route to macrolide antibiotics that bypasses many of the limitations of semisynthesis. Andrew Myers and colleagues describe a fully synthetic route to macrolide antibiotics via the convergent assembly of simple chemical building blocks. More than 300 new antibiotic candidates were synthesized using this approach, some of which are active against bacterial strains that are resistant to currently used antibiotics.

Autonomous laboratories can accelerate discoveries in chemical synthesis, but this requires automated measurements coupled with reliable decision-making 1 , 2 . Most autonomous laboratories involve bespoke automated equipment 3 – 6 , and reaction outcomes are often assessed using a single, hard-wired characterization technique 7 . Any decision-making algorithms 8 must then operate using this narrow range of characterization data 9 , 10 . By contrast, manual experiments tend to draw on a wider range of instruments to characterize reaction products, and decisions are rarely taken based on one measurement alone. Here we show that a synthesis laboratory can be integrated into an autonomous laboratory by using mobile robots 11 – 13 that operate equipment and make decisions in a human-like way. Our modular workflow combines mobile robots, an automated synthesis platform, a liquid chromatography–mass spectrometer and a benchtop nuclear magnetic resonance spectrometer. This allows robots to share existing laboratory equipment with human researchers without monopolizing it or requiring extensive redesign. A heuristic decision-maker processes the orthogonal measurement data, selecting successful reactions to take forward and automatically checking the reproducibility of any screening hits. We exemplify this approach in the three areas of structural diversification chemistry, supramolecular host–guest chemistry and photochemical synthesis. This strategy is particularly suited to exploratory chemistry that can yield multiple potential products, as for supramolecular assemblies, where we also extend the method to an autonomous function assay by evaluating host–guest binding properties. A modular autonomous platform for general exploratory synthetic chemistry uses mobile robots to integrate an automated synthesis platform and two analysis platforms.