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Mining antibiotic andrimid to fight multidrug-resistant bacteria

Mining and utilizing andrimid, a novel antibiotic targeting multidrug-resistant bacteria, presents a strategic solution amidst the rise of antibacterial superbugs.

Penicillin, discovered in 1928 by British bacteriologist Alexander Fleming, was the first antibiotic in the world. While initially effective against bacterial infections, its efficacy waned over time as bacteria became more resistant to penicillin. Subsequent abuse of multiple antibiotics resulted in the proliferation of several types of drug-resistant bacteria. These bacteria pose a serious public health threat to the medical, agricultural, and industrial sectors.

Why do we need new antibiotics?

Antibiotic resistance is an increasingly serious public health threat. Without collaborative efforts to address this issue, we risk entering an era threatened by multidrug-resistant bacteria. This could potentially compromise the progress of modern medicine, leading to a resurgence of infection-related deaths. Modeling by Rebecca Sugden et al. (shown below) predicts a significant rise in deaths caused by multidrug-resistant bacteria worldwide by 2050. Failure to develop new antibiotics could compromise our ability to treat infections effectively in the future.

A report from the World Health Organisation highlights a crucial issue. Despite the growing awareness of the threat of antibiotic resistance, the world has yet to develop much-needed new antimicrobial treatments.

Developing novel antibiotics is, therefore, critical in tackling bacterial resistance, ensuring effective infection treatment, and safeguarding public health. Consequently, researchers have been working hard to develop new antibacterial drugs, with andrimid, which has non-traditional targets, being a topic of significant interest in the field. Andrimid is a promising antibiotic that inhibits the growth of prokaryotic cells by hindering the biosynthesis of fatty acids.

Figure 1: Number of antibiotic resistance-related deaths in each continent.
Credit. Rebecca Sugden

What is andrimid?

The study of andrimid has a longstanding history. The andrimid compound was initially isolated from the fermentation broth of a symbiotic bacterium of the brown planthopper in 1987. It showed a notable inhibitory effect on the bacterial pathogen of rice blight. In 2002, Bayer achieved chemical synthesis of andrimid. However, the high cost of chemical synthesis hindered industrial-scale production.

However, advancements in molecular technology led to scientists identifying the biosynthetic gene cluster in 2006. This laid the foundation for further research on andrimid.

It’s a promising antibiotic that prevents the growth of prokaryotic cells by hindering fatty acid biosynthesis. This is achieved by inhibiting the β-subunit of acetyl coenzyme A carboxylase, a key enzyme responsible for converting acetyl coenzyme A to malonyl coenzyme A, which is essential for microbial growth.

These characteristics make andrimid effective against multi-drug-resistant bacteria. The compound is harmless to the human body due to the differing fatty acid synthase of eukaryotes and prokaryotes, enhancing its clinical applicability.

Previously, researcher Dr Zhao and his laboratory team isolated a bacterium named Erwinia persicina BST187 from the rhizosphere soil of tomatoes. After detection, subsequent analysis revealed that this strain could also produce andrimid. Further assessment through bacterial inhibition testing demonstrated that the BST187 strain exhibits a highly effective inhibitory effect on bacteria.

Figure 2. The effectiveness of various antibiotic drugs against bacteria.
Credit. Xinyue Zhao

Importance of the investigated gene admX

Industrial production and utilization of andrimid is severely hampered by the low yields of all its production strains. To tackle this problem, two promising strategies emerged: engineering the biosynthetic pathway and optimizing fermentation. Genetic engineering modifications contribute to increasing andrimid production and industrial development, as well as expanding the microbial drug resource pool. In addition, they help alleviate strain resistance issues and provide better protection for human health and the ecological environment.

When addressing the application of modern biotechnology in microbial modification, genetic engineering is worth mentioning. It has become a widely employed strategy for optimizing substrate utilization and product generation rates by altering the metabolic pathways of microorganisms. For example, through gene editing and modulation, we can enhance the ability of microorganisms to absorb and transform substrates, thereby increasing yields. Moreover, when performing strain modification, targeted key steps in the metabolic pathway often yield significant improvements.

Within the BST 187 strain, there is a gene called admX which plays an important role in regulating andrimid production. Dr Zhao’s laboratory team observed that adjusting the expression level of the admX gene significantly impacts andrimid synthesis. Gradually increasing admX gene expression can significantly increase andrimid yield. However, excessive expression of admX resulted in decreased yield.

The significance of the study on andrimid

The findings of this study are important for andrimid production and optimisation because it reveals how to balance gene expression levels for optimal yield during synthesis. In the subsequent study, the researcher obtained a new high-yielding strain by regulating the expression level of admX: BST187ΔadmX/pET28a-Pgap-1::admX. This modification resulted in a 260% increase in andrimid yield over 18 hours of fermentation.

This study provides important insights into the biosynthetic mechanism of andrimid, deepening our understanding of its production process. It also highlights the potential applications of andrimid in biomedical and bio-agricultural fields.

In the future, these discoveries will pave the way for large-scale production of andrimid, offering improved solutions for combating infections and diseases. The ongoing exploration of andrimid continues, with scientists committed to further exploration to maximize the potential of this potent antibiotic.

Figure 3: Animated image of andrimid combating bacteria
Credit. Sohu.com

Conclusion

Research on andrimid not only enhances our understanding of the biosynthetic mechanisms of antibiotics but also opens up a new path for antibiotic discovery. More importantly, this study demonstrates the viability of genetic engineering in increasing andrimid production, providing new ideas for production optimization and industrial development. In addition, it instills confidence in the exploration and utilization of new natural products.

Through continuous exploration, we may uncover more valuable resources similar to andrimid, further benefiting human health. For the further development of the new antibiotic, the mining of new antibiotics, such as glycopeptide antibiotics extracted from Streptomyces, may serve as a reserve resource for combating multidrug-resistant bacteria. Besides, The development and modification of new antibiotic drugs are an important part of global health and safety issues. At present, non-ribosomal peptide polyketone compounds may be able to adapt to the evolution of drug resistance by modifying different structural domains, while internal gene modifications are very interesting.

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Journal reference

Zhao, L., Ge, T., Cheng, T., Wang, Q., Cui, M., Yuan, H., & Zhao, L. (2023). Fine-tuning gene expression of regulator AdmX for improved biosynthesis of andrimid in Erwinia persicina BST187. Applied Microbiology and Biotechnology107(22), 6775-6788. https://doi.org/10.1007/s00253-023-12770-3

Lei Zhao is a professor at the Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences. His primary research lies in the artificial design and creation of low-carbon synthetic biological systems. The research includes the discovery, design, and modular assembly of important functional components. Additionally, he is involved in the integrated application of principles and methods of genetics, cell biology, and synthetic biology. The goal is to design and modify important chassis cells for green biomanufacturing, enabling the production of high-value-added chemicals, recombinant proteins, and natural products.

Xinyue Zhao is a master’s student at the University of Chinese Academy of Sciences, Sino-Danish College. Her research focuses on novel antibiotics.

Tingfeng Cheng is a PhD candidate at the Tianjin Institute of Industrial Biotechnology of the Chinese Academy of Sciences. His research interests include microbiology and molecular biology.