Highlights
- There is a crisis of antibiotic resistance that is compounded by the lack of new antibiotics being developed.
- A plant toxin known as albicidin is a promising new antibiotic candidate.
- Researchers have used structural biology to show how albicidin inhibits bacterial enzymes known as DNA gyrase and topoisomerase IV, which are essential for bacterial DNA replication.
One of the most pressing problems in medicine is antibiotic resistance—where microorganisms evade treatment with multiple drugs, leading to superinfections that can be difficult or impossible to cure. Now, a multinational team of scientists has solved the structure of albicidin, an antibiotic made by a plant pathogen that may prove to be effective against bacterial species that are resistant to other antibiotics. The work, published in Nature Catalysis, reveals the function of albicidin, which may help researchers improve the compound’s clinical potential.
The Challenges
In 2019, according to the U.S. Centers for Disease Control and Prevention, nearly 1.3 million people died from antibiotic resistant infections worldwide. Antibiotic resistance spreads when most of an infection is cleared but the resistant microbes survive and multiply, converting the entire population to one that isn’t susceptible to the drugs, or when antibiotic resistant bacteria pass the gene for resistance to other microbes. Antibiotic misuse and overuse in healthcare and agriculture can also increase antibiotic resistance, as the more microbes are exposed to antibiotics, the more microbes have an opportunity to develop resistance.
Antibiotic resistance is also growing worldwide. In a December 2022 report, the World Health Organization showed an increase in resistance in bacteria that cause bloodstream, urinary tract, and genital infections. Despite the growing need for new antibiotics, the return on investment for companies that develop antibiotics is low to non-existent. Large pharmaceutical companies like Novartis have stopped developing antibiotics and several smaller startups in the space have gone bankrupt.
Structure Informs Function
Based on these challenges, new antibiotic possibilities generate excitement. Albicidin was originally discovered in the 1980s and is made by a bacterium that causes the plant disease known as leaf scald, which can destroy entire crops of sugarcane. Since its discovery, ongoing research has accelerated the possibility that it can be used as an antibiotic in the clinical setting.
Prior studies showed that albicidin inhibits DNA gyrase and DNA topoisomerase IV, heart-shaped enzymes that bacteria need to copy their DNA. These are popular enzymes for antibiotics to target because without correct enzyme function, bacteria can’t grow. One class of antibiotics, the fluoroquinolones, turn DNA gyrase into a toxin that kills bacterial cells, but cases of antibiotic resistance are common, and the antibiotic can damage mammalian cells as well.
The authors of the Nature Catalysis study had previously shown that albicidin is a molecule with six components and made a synthetic version of the compound and several derivatives in the lab. Having a new option in albicidin to target these bacterial enzymes could mean less damage to mammalian cells and thus greater clinical promise, but one remaining question as to how albicidin works needed to be answered.
The research team used cryoelectron microscopy—where samples are flash frozen and then viewed with an electron microscope—to visualize how albicidin interacts with DNA gyrase and DNA molecules. They found that albicidin requires DNA to be bound to the enzyme in order to interact and also that albicidin binds strongly to the part of DNA gyrase that cleaves bacterial DNA in order to relieve strain during replication. The authors also showed that a mutation in DNA gyrase that confers bacterial resistance to fluoroquinolones did not affect the efficiency of albicidin binding, meaning that albidicin and its derivatives may provide a solution in cases of fluoroquiniolone resistance. Finally, they determined that albicidin and two derivatives created in the lab also bind to topoisomerase IV, the bacterial enzyme responsible for untangling DNA after replication, suggesting that albicidin may be effective in targeting both enzymes.
Understanding the structures of albicidin and its interactions with bacterial enzymes, the authors wrote, “allow us to pinpoint the pharmacophores responsible for molecular recognition, and thus to rationally design variants of the toxin to overcome resistance mutations or to improve pharmacological properties of compounds such as their solubility, without affecting target binding. These findings are indispensable for the structure-guided development of albicidins as next-generation antimicrobial therapeutics.”
The Future
The next steps in developing albicidin and related drugs into viable candidates to address the antibiotic resistance crisis include improving their solubility, ability to get into bacterial cells, and stability, as well as addressing potential toxicity toward eukaryotic topoisomerase II. While DNA gyrase and topoisomerase IV are unique to bacteria, eukaryotic topoisomerase II performs a similar untangling function in mammalian cells, raising the possibility that albicidin could affect this enzyme and disrupt human cells.
Despite the hurdles ahead, the findings show promise. As Tony Maxwell, who investigates topoisomerases at the John Innes Centre in the UK and did not participate in the study, told The Guardian, “This work, which opens up a whole new range of drugs based on our new understanding of how albicidin works, has got to be good news. It may take years to create clinically effective versions, but it does suggest we may have a new weapon in our armory one day.”
References
- About Antimicrobial Resistance, Centers for Disease Control and Prevention, 5 October 2022.
- Broadwith, P., “Explainer: What is cryo-electron microscopy,” Chemistry World, 4 October 2017.
- Cociancich, S. et al., “The gyrase inhibitor albicidin consists of p-aminobenzoic acids and cyanoalanine,” Nature Chemical Biology, 2015.
- Global antimicrobial resistance and use surveillance system (GLASS) report: 2022, World Health Organization, 9 December 2022.
- Jacobs, A. “Crisis Looms in Antibiotics as Drug Makers Go Bankrupt,” New York Times, 26 December 2022.
- Lewis K., “The Science of Antibiotic Discovery,” Cell, 2020.
- Mc Kie, R., “Plant toxin hailed as ‘new weapon’ in antibiotic war against bacteria,” The Guardian, 29 January 2023.
- Michalczyk, E. et al., “Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin,” Nature Catalysis, 2023.