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AMPGAN v2: Machine Learning-Guided Design of Antimicrobial Peptides.

ABSTRACT: Antibiotic resistance is a critical public health problem. Each year ∼2.8 million resistant infections lead to more than 35 000 deaths in the U.S. alone. Antimicrobial peptides (AMPs) show promise in treating resistant infections. However, applications of known AMPs have encountered issues in development, production, and shelf-life. To drive the development of AMP-based treatments, it is necessary to create design approaches with higher precision and selectivity toward resistant targets. Previously, we developed AMPGAN and obtained proof-of-concept evidence for the generative approach to design AMPs with experimental validation. Building on the success of AMPGAN, we present AMPGAN v2, a bidirectional conditional generative adversarial network (BiCGAN)-based approach for rational AMP design. AMPGAN v2 uses generator-discriminator dynamics to learn data-driven priors and controls generation using conditioning variables. The bidirectional component, implemented using a learned encoder to map data samples into the latent space of the generator, aids iterative manipulation of candidate peptides. These elements allow AMPGAN v2 to generate candidates that are novel, diverse, and tailored for specific applications, making it an efficient AMP design tool.

SUBMITTER: Van Oort CM

PROVIDER: S-EPMC8281497 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCurrent methods in machine learning provide approaches for solving challenging, multiple constraint design problems. While deep learning and related neural networking methods have state-of-the-art performance, their vulnerability in decision making processes leading to irrational outcomes is a major concern for their implementation. With the rising antibiotic resistance, antimicrobial peptides (AMPs) have increasingly gained attention as novel therapeutic agents. This challenging design problem requires peptides which meet the multiple constraints of limiting drug-resistance in bacteria, preventing secondary infections from imbalanced microbial flora, and avoiding immune system suppression. AMPs offer a promising, bioinspired design space to targeting antimicrobial activity, but their versatility also requires the curated selection from a combinatorial sequence space. This space is too large for brute-force methods or currently known rational design approaches outside of machine learning. While there has been progress in using the design space to more effectively target AMP activity, a widely applicable approach has been elusive. The lack of transparency in machine learning has limited the advancement of scientific knowledge of how AMPs are related among each other, and the lack of general applicability for fully rational approaches has limited a broader understanding of the design space.MethodsHere we combined an evolutionary method with rough set theory, a transparent machine learning approach, for designing antimicrobial peptides (AMPs). Our method achieves the customization of AMPs using supervised learning boundaries. Our system employs in vitro bacterial assays to measure fitness, codon-representation of peptides to gain flexibility of sequence selection in DNA-space with a genetic algorithm and machine learning to further accelerate the process.ResultsWe use supervised machine learning and a genetic algorithm to find a peptide active against S. epidermidis, a common bacterial strain for implant infections, with an improved aggregation propensity average for an improved ease of synthesis.ConclusionsOur results demonstrate that AMP design can be customized to maintain activity and simplify production. To our knowledge, this is the first time when codon-based genetic algorithms combined with rough set theory methods is used for computational search on peptide sequences.

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AMPGAN v2: Machine Learning-Guided Design of Antimicrobial Peptides.

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