Generative AI for designing and validating easily synthesizable and structurally novel antibiotics

Abstract

The rise of pan-resistant bacteria is creating an urgent need for structurally novel antibiotics. Artificial intelligence methods can discover new antibiotics, but existing methods have notable limitations. Property prediction models, which evaluate molecules one-by-one for a given property, scale poorly to large chemical spaces. Generative models, which directly design molecules, rapidly explore vast chemical spaces but generate molecules that are challenging to synthesize. Here we introduce SyntheMol, a generative model that designs new compounds, which are easy to synthesize, from a chemical space of nearly 30 billion molecules. We apply SyntheMol to design molecules that inhibit the growth of Acinetobacter baumannii, a burdensome Gram-negative bacterial pathogen. We synthesize 58 generated molecules and experimentally validate them, with six structurally novel molecules demonstrating antibacterial activity against A. baumannii and several other phylogenetically diverse bacterial pathogens. This demonstrates the potential of generative artificial intelligence to design structurally novel, synthesizable and effective small-molecule antibiotic candidates from vast chemical spaces, with empirical validation.