Accelerating Antimicrobial Discovery with Controllable Deep Generative Models and Molecular Dynamics
This work addresses the problem of antibiotic resistance by accelerating the discovery of broad-spectrum antimicrobials, representing a strong specific gain in therapeutic design.
The authors tackled the challenge of designing antimicrobial peptides with high potency and low toxicity by proposing CLaSS, a deep generative method for controllable molecule generation, which identified two novel peptides effective against diverse pathogens, including resistant strains, with low toxicity.
De novo therapeutic design is challenged by a vast chemical repertoire and multiple constraints, e.g., high broad-spectrum potency and low toxicity. We propose CLaSS (Controlled Latent attribute Space Sampling) - an efficient computational method for attribute-controlled generation of molecules, which leverages guidance from classifiers trained on an informative latent space of molecules modeled using a deep generative autoencoder. We screen the generated molecules for additional key attributes by using deep learning classifiers in conjunction with novel features derived from atomistic simulations. The proposed approach is demonstrated for designing non-toxic antimicrobial peptides (AMPs) with strong broad-spectrum potency, which are emerging drug candidates for tackling antibiotic resistance. Synthesis and testing of only twenty designed sequences identified two novel and minimalist AMPs with high potency against diverse Gram-positive and Gram-negative pathogens, including one multidrug-resistant and one antibiotic-resistant K. pneumoniae, via membrane pore formation. Both antimicrobials exhibit low in vitro and in vivo toxicity and mitigate the onset of drug resistance. The proposed approach thus presents a viable path for faster and efficient discovery of potent and selective broad-spectrum antimicrobials.