Advances in High-Throughput Screening for Novel Antimicrobial Compounds

Drug and therapeutic development requires the effective screening of vast numbers of target compounds in a short period of time. In recent decades, high-throughput screening has provided researchers and pharmaceutical companies with unparalleled capabilities in drug discovery for novel antibiotic compounds and other types of therapeutics. 

​​​​​​​Image Credit: fongbeerredhot/​​​​​​​Image Credit: fongbeerredhot/

High-Throughput Screening: Foundations and Techniques

High-throughput screening (HTS) involves screening vast libraries of potential drug targets made up of a myriad of small molecules and other complex compounds. Various scientific breakthroughs have meant that HTS methods have become increasingly miniaturized, automated, and standardized, leading to vastly improved drug discovery capabilities in multiple laboratories worldwide.

HTS relies on a number of key technologies such as robotics, automation, miniaturization, and large-scale data analytics in order to provide researchers with the ability to analyze thousands of potential drug targets in a fraction of the time of traditional screening methods.

Alongside the various HTS screening technologies employed in clinical laboratories such as in vitro biochemical assays, cell-based assays, and RNA interference screening, related advances in fields such as data analysis have led to faster, reproducible, and more reliable screening results.1

What is High Throughput Screening?

Advances in HTS Technologies

The development of reliable automated systems was largely necessary to make HTS commercially feasible. Specifically, automated liquid handling systems were one of the lightbulb moments in the development of this crucial screening approach. With automated liquid handling systems, laboratories could process thousands of parallel samples at once in a time- and cost-efficient manner.

Automated workflows allow scientists to improve screening quality and reproducibility without the need for manual intervention and supervision. Another key breakthrough was the development of microfluidic systems, which use a small volume of purified compounds in high-density arrays. In these systems, screening rates are improved while the amount of reagent is reduced.

Microfluidic channels can also mimic the complex, interconnected nature of biological systems by allowing the construction of interconnected compartments. Furthermore, 3D cell culture allows researchers to build organoids (miniature organs) that can more effectively replicate structures within the human body than 2D cell lines or animal models.

Automated and live cell imaging methods have also emerged in recent years, allowing more detailed information to be captured during HTS analysis and improving high-content screening capabilities. Multi-imaging and labeling techniques can provide insights into morphological and signaling changes and the simultaneous study of multiple properties in individual cells.

Precise gene editing techniques such as CRISPR-Cas9 are amenable to HTS approaches as they can be used to design custom libraries. DNA-encoded libraries also allow screening large compound libraries by barcoding genetic sequences.1 AI, machine learning, and cell-free assays are also emerging as key technologies in this area.

HTS in the Search for Antimicrobial Compounds

More than 50% of current antimicrobial products on the market are derived from natural products, but there is a key issue surrounding their use: namely, that of emerging drug resistance. There is also a lack of new and promising antimicrobials in the drug discovery pipeline, which presents a major public health challenge.

Therefore, new antimicrobial therapeutics need to be found. HTS can rapidly screen natural and synthetic molecule libraries for potential antibiotics and antimicrobials, providing researchers with new potential targets that can be tested in the lab.

Natural sources of potential molecules that can be used as antimicrobials are still vastly preferred in drug discovery assays due to factors such as diverse chemical natures and spatial arrangements. Furthermore, only a small number of the vast untapped potential natural targets have been screened so far, making them ideal for HTS methods which can significantly speed up drug discovery.

One notable success in this area was the use of microfabricated chips to discover a previously unknown anti-MRSA agent, teixobactin. 10,000 isolates were screened to discover this antimicrobial therapeutic. Other notable drug discovery platforms made possible by HTS include BioMap and Compound Activity Mapping.2

Challenges in HTS for Antimicrobials

Some key challenges remain, which make employing HTS for antimicrobial discovery complex despite its huge potential. For instance, the presence of cytotoxic compounds in assays can obscure potential therapeutic targets, requiring purification of the sample, a reset, and the use of cytotoxicity assays to retrieve reliable results.2 Additionally, the action of bioactive compounds can make further purification necessary.

There can also be a high rate of false positives in analyses, which can skew results. Researchers must account for these and may require further testing to eliminate them. Furthermore, translating in vitro findings to clinical applications can be highly challenging. Some solutions to these problems could include using more physiologically relevant models or combinatorial chemistry.

Integrating HTS with Other Discovery Approaches

Despite its benefits, relying on HTS alone may not provide researchers with a holistic understanding of potential drug targets. Integrating HTS approaches with other methods, such as omics-based drug discovery, could benefit clinical research.

One such approach is integrating HTS with Fragment-Based Drug Discovery (FBDD).3 This complementary approach would leverage both HTS's rapid discovery potential and FBDD’s ability to systematically probe enzyme targets. Several papers and projects have explored this potential approach to drug discovery, which could benefit the development of new antimicrobial drugs.

Future Directions in HTS for Antimicrobial Research

There are several promising future avenues in HTS and antimicrobial discovery. Ongoing advances in data analysis, AI, machine learning, and technologies such as microfluidics, nanofluidics, and imaging-based techniques could be game changers in this area.

Increasingly, non-traditional sources of novel compounds are being analyzed and exploited, and the use of microbial consortia for more realistic screening environments could also prove beneficial in HTS methods for antimicrobial drug target discovery. 

In Conclusion

In summary, HTS technologies and approaches have found profound applications in multiple clinical research fields, vastly improving screening rates and drug discovery from both natural and synthetic sources. Recent research has attested to the success of employing HTS methods, with some potential therapies, such as those that could help combat drug-resistant bacteria, being discovered in the past few years.

With the rise of drug-resistant microbes, there is an urgent need to rapidly and comprehensively speed up the discovery of potential therapeutics from vast untapped libraries. HTS approaches are ideally suited to this task, whether used alone or in combination with other complementary drug discovery approaches.


Further Reading

Last Updated: May 30, 2024

Reginald Davey

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Reginald Davey

Reg Davey is a freelance copywriter and editor based in Nottingham in the United Kingdom. Writing for AZoNetwork represents the coming together of various interests and fields he has been interested and involved in over the years, including Microbiology, Biomedical Sciences, and Environmental Science.


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