Artificial Intelligence and new Antibiotic discovery

By | April 25, 2024

The Global Threat of Antimicrobial Resistance

Antimicrobial resistance poses a serious global threat as some bacterial infections are becoming increasingly difficult, and sometimes impossible, to treat due to the emergence and spread of drug-resistant microorganisms. According to the World Health Organization, antimicrobial resistance is one of the top 10 global public health threats facing humanity. If no action is taken, drug-resistant diseases could cause 10 million deaths each year by 2050 and damage to the global economy as high as $100 trillion.

Our existing antibiotics are losing their effectiveness at an alarming rate as bacteria continue to develop resistance to them. At the same time, major pharmaceutical companies have largely withdrawn from antimicrobial drug research and development in recent decades due to high costs and failure rates. As a result, the pipeline of new classes of antibiotics is practically dry. With few new drugs in development, we face the disturbing possibility of entering a “post-antibiotic era” where common infections and minor injuries that have been treatable for decades could once again kill. This crisis demands urgent action and innovation.

AI Shows Promise in Antibiotic Discovery

Fortunately, artificial intelligence may offer a powerful new tool to address this crisis by accelerating the antibiotic discovery process. AI and machine learning algorithms have the potential to screen huge databases of chemical structures and identify novel compounds with antimicrobial properties much more rapidly than human researchers alone. They can also provide insights into how different molecules interact with bacterial targets on a molecular level to inform drug design. Here are some specific ways AI is starting to aid antibiotic discovery efforts:

– Chemical Structure Screening – AI analyzes immense databases containing millions of potential drug-like small molecules, rapidly evaluating their characteristics and likelihood of inhibiting microbial growth or specific bacterial targets. It can screen far more candidate structures much faster than humans.

– Target Identification – AI-based methods like deep learning aid in determining the mechanisms of antibiotic resistance in bacterial strains, helping uncover novel targets for drug intervention. They can analyze patterns in vast genetic sequence data.

– Lead Compound Optimization – Once an initial “hit” compound showing antimicrobial activity is discovered, AI aids the optimization process of modifying its chemical structure to improve potency, oral bioavailability, and safety profile through iterative testing.

– Generating Hypotheses – Deep learning is leveraged to generate new hypotheses about bacterial proteins and pathways that could serve as fresh antibiotic targets. Algorithms identify unseen patterns and generate ideas from existing research data.

– Predicting Drug Properties – Machine learning predicts important properties of lead candidate drugs like absorption, distribution, metabolism, excretion, and toxicity early in development to inform decisions and accelerate candidate selection.

– Repurposing Existing Drugs – AI technologies can analyze molecular, genetic, and clinical data to discover existing drugs approved for other diseases that may also have untapped antimicrobial activity against pathogens, expediting their development as new classes of antibiotics.

AI Accelerates Progress at Startups and Nonprofits

Here are some examples of biotech startups and nonprofit initiatives using AI for antibiotic discovery:

Biotech Startups:

Insilico Medicine – Uses generative adversarial networks and reinforcement learning to generate novel molecular structures with antibiotic properties.

Anthropic – Applies self-supervised learning techniques like contrastive predictive coding to antibiotic target and drug design.

BenevolentAI – Develops AI platforms like PBC Quest and Clinithink to accelerate antibiotic and antimicrobial research.

Cyclica – Leverages graph-based machine learning models to discover potential drugs and analyze mechanisms of action.

Quratis – Applies deep learning to genomic data to predict antibiotic resistance, determinants, and virulence factors.

Nonprofit Initiatives:

– PBC Antimicrobial Resistance Project – Applies generative modeling to design new β-lactam therapies targeting critical pathogens.

CARB-X – Partners with AI startups like Anthropic, subsidizes early research on antibiotics against priority drug-resistant germs.

Broad Institute of MIT – Collaborated on applying deep learning to predict and disrupt resistance mechanisms.

Wellcome Trust – Funded initiatives leveraging AI for genomic sequencing analysis and antibiotic target prediction.

– Joint Initiative from WHO, FAO, OIE – Launched global projects enhancing surveillance data for better AI/ML model training.

DeepMind-Lausanne Hospital – Partnered to develop algorithms analyzing bacterial patterns from clinical samples.

Geometric therapeutics at UC San Diego – Uses graph neural networks to design antibiotics attacking pathogen interactions.

So in summary, both private startups and nonprofit groups are actively pursuing innovative AI strategies for antibiotic R&D.

how Insilico Medicine uses generative adversarial networks (GANs) and reinforcement learning in antibiotic discovery:

Generative Adversarial Networks:

– Insilico trains a GAN model on large chemical/genomic datasets of biologically relevant molecules.

– The generator network creates new candidate molecular structures based on patterns it learns.

– The discriminator network evaluates candidates, providing feedback to generator on similarity to known drugs/properties.

– Over iterations, the generator improves at producing novel structures with desired traits like antibiotic activity.

– This allows effectively exploring the vast chemical space beyond what can be synthesized experimentally.

Reinforcement Learning:

– Another AI model acts as the “agent” tasked with generating antibiotic molecule structures.

– The environment provides rewards/penalties based on predicted performance against pathogens.

– Properties like cytotoxicity, bioavailability, resistance potential affect the reward structure.

– The agent aims to maximize total reward by learning which molecular modifications lead to higher scores.

– This simulates a medicinal chemistry optimization process to develop leads into drug candidates.

Together, these techniques:

– Rapidly propose vast numbers of novel molecular structures.

– Guide modifications towards optimal antibiotic properties through feedback.

– Circumvent traditional, slower experimental synthesis methods.

– Discover molecules outside what human intuition or databases could find alone.

This accelerates candidate evaluation and optimization through extensive in silico testing before wet lab validation.

Here are some key advantages of using generative adversarial networks (GANs) and reinforcement learning in antibiotic discovery compared to traditional methods:

Speed and Scale
– They can evaluate millions+ of molecules virtually, much faster than physical synthesis and testing in labs. This dramatically improves screening throughput.

– AI models can propose entirely novel molecular structures beyond what researchers or existing databases contains. This expands the search space beyond human intuition.

Optimization Guidance
– Reinforcement learning actively guides molecular modifications toward optimized properties, simulating a medicinal chemistry process in silico.

Data-Driven Approach
– Models leverage immense datasets to detect patterns and propose candidates informed by a wealth of genomic and molecular data, beyond a few research intuitions or hypotheses.

Reduced Costs
– In silico testing reduces expensive physical synthesis and analysis costs during early candidate identification and optimization stages.

– Multiple algorithm iterations and candidate evaluations can run simultaneously, allowing properties of millions of molecules to be analyzed in parallel.

Rapid Design-Test Loop
– The AI drug design and testing cycle is highly sped up compared to traditional chemical synthesis and experimentation workflows. Models incorporate results much faster.

Minimized Animal Testing
– In silico screening and optimization reduces need for animal studies during early development, addressing ethical concerns. Results better inform downstream studies.

Some potential downstream studies that can be informed by results from in silico screening and optimization through techniques like generative adversarial networks and reinforcement learning include:

– In vitro testing – Test top lead candidates generated in silico against pathogens in lab cultures to validate antimicrobial activity predictions.

– Physiochemical analysis – Characterize leads through techniques like chromatography to confirm properties like solubility, stability, permeability predicted computationally.

– ADME studies – Conduct absorption, distribution, metabolism, excretion tests on candidates to verify pharmacokinetic profiles predicted in silico.

– Toxicology analysis – Test for cytotoxicity against mammalian cells or organ/tissue samples to validate safety predictions.

– Mechanism of action studies – Use techniques like DNA microarrays, protein characterization assays to confirm predicted inhibitory mechanisms.

– Drug resistance profiling – Experimentally determine how easily pathogens could develop resistance to lead candidates.

– Pharmacodynamic modeling – Build mathematical models of antimicrobial effects based on in vitro/vivo data to optimize dosing.

– Animal efficacy testing – Test most promising leads in infection models to demonstrate safety and antimicrobial activity in vivo.

– Clinical candidate selection – Choose a candidate backed by in vitro, in vivo data to progress towards clinical trials for further studies in humans.

The results of in silico work help prioritize and guide subsequent resource-intensive wet lab and animal validation required for developing a new antibiotic. It represents a major portion of the overall discovery process.

Outlook for AI in Antibiotic Development

While still in early stages, AI shows enormous promise in revolutionizing antibiotic discovery. By sifting through massive chemical and genomic data in silico, AI allows exploring viable drug candidates that may have been previously overlooked by researchers. It also streamlines optimization of lead compounds. As these technologies mature and benefit from more training data, their ability to help researchers systematically interrogate microbial systems and design novel inhibitor classes will greatly amplify traditional approaches.

There remain challenges to optimize predictive algorithms and integrate AI into real-world workflows. Rigorous experimental validation of computer-suggested molecules will also be needed. With further development and adoption, however, AI is increasingly seen as crucial to revitalizing the antibiotic pipeline and meeting the global crisis of antimicrobial resistance. By enhancing every stage of the discovery process through deep analysis of massive data, AI facilitates ongoing scientific innovation against this critical threat to public health security worldwide.