March 2, 2024

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AM-2-19 Offers Safe and Effective Alternative to Amphotericin B

Breakthrough in Antifungal Treatment: AM-2-19 Offers Safe and Effective Alternative to Amphotericin B



Breakthrough in Antifungal Treatment: AM-2-19 Offers Safe and Effective Alternative to Amphotericin B

According to statistics, approximately 1.5 million people die from fungal infections worldwide each year.

Unfortunately, antifungal drugs are not only scarce (only three types), but each type faces issues such as human toxicity, increased drug resistance, or limited efficacy.

Discovered in 1955, the antifungal drug Amphotericin B (AmB) is a potent agent against fungi and is less prone to developing resistance. However, AmB has strong renal toxicity, making it the last line of defense against human fungal infections.

Recently, a research team led by Martin D. Burke from the University of Illinois Urbana-Champaign and Chad M. Rienstra from the University of Wisconsin-Madison published a groundbreaking study in the top journal “Nature.”

Breakthrough in Antifungal Treatment: AM-2-19 Offers Safe and Effective Alternative to Amphotericin B

After more than a decade of exploration, they have found a way to improve AmB. Their modified version, AM-2-19, can kill over 500 types of fungi, demonstrating comparable or superior therapeutic effects to AmB. Importantly, even at the maximum dosage, AM-2-19 has no harmful effects on the kidneys.

Currently undergoing clinical trials, AM-2-19 could revolutionize the field of antifungal treatment if successful.

As mentioned earlier, AmB has been in clinical use as an antifungal drug since 1959.

Despite its long history, scientists have not fully understood AmB’s mechanism of action for almost half a century. The mainstream view suggests that after penetrating the fungal cell wall, AmB binds with ergosterol in the fungal cell membrane, forming pores that lead to substance leakage and fungal cell death.

However, Burke’s team, in a 2012 study, challenged this view, indicating that the holes in the cell membrane were not crucial to AmB’s fungicidal process; instead, the crucial factor was AmB’s binding with ergosterol.

Breakthrough in Antifungal Treatment: AM-2-19 Offers Safe and Effective Alternative to Amphotericin B

Schematic diagram of AmB removing ergosterol and cholesterol from cell membranes

Over the following years, Burke’s team collaborated with Rienstra’s team to refine their AmB killing model. Their research indicated that AmB acts like a magnet, pulling ergosterol out of the fungal cell membrane, causing changes in membrane permeability and promoting fungal death.

Simultaneously, the mechanism of AmB’s renal toxicity emerged. Similar to ergosterol in the fungal cell membrane, AmB also extracts cholesterol from human cell membranes.

After discovering this secret, Burke’s team attempted to modify AmB, creating various derivatives, but none were both safe and effective.

When Burke’s team faced a dead end, Rienstra’s team brought good news. As experts in solid-state nuclear magnetic resonance, Rienstra and his team obtained high-resolution images of AmB binding with ergosterol and cholesterol.

The atomic-level resolution model allowed the researchers to see the true nature of AmB’s binding with ergosterol and cholesterol. It turned out that the binding conformation with ergosterol and cholesterol was highly similar, explaining the previous failures. The good news was that AmB had a higher affinity for ergosterol than cholesterol. This meant there was still hope to prevent AmB from binding to cholesterol.

After in-depth analysis of imaging data, they found that swapping one hydrogen atom and one hydroxyl group in AmB (C2′epiAmB) could prevent AmB from binding to cholesterol. Experimental results showed that this new compound no longer bound to cholesterol, while retaining its ability to bind with ergosterol. Even at the highest dosage, it had no detrimental effects on the kidneys.

Breakthrough in Antifungal Treatment: AM-2-19 Offers Safe and Effective Alternative to Amphotericin B

New compound (C2′epiAmB) does not cause kidney cell death

Unfortunately, success did not come quickly.

Burke and Rienstra’s team found that AmB’s binding ability with ergosterol also weakened. This weakening would slow down the extraction of ergosterol from the fungal cell membrane. For fungi that synthesize ergosterol quickly, AmB’s antifungal ability would decrease.

To prevent their previous work from going to waste, Burke and Rienstra’s team attempted to enhance the speed of AmB extracting ergosterol on the current basis. This way, they could disrupt the balance of ergosterol in the fungal cell membrane, achieving the effect of destroying the cell membrane.

So, they went back to analyzing high-resolution images.

Their efforts paid off. They found that by adjusting one carboxylic acid group, they could speed up the extraction of ergosterol by AmB derivatives. Thus, Am-2-19 was born.

Breakthrough in Antifungal Treatment: AM-2-19 Offers Safe and Effective Alternative to Amphotericin B

Am-2-19 himself

Experimental data showed that AM-2-19 could bind with ergosterol but not with cholesterol. It could extract ergosterol from the fungal cell membrane more rapidly, killing the fungi. Moreover, AM-2-19 was non-toxic to primary human kidney cells and other mammalian cells, causing no damage to mouse kidneys.

Fast extraction speed can destroy the fungal cell membrane

After obtaining these research results, Burke and Rienstra’s team sent AM-2-19 to four other laboratories to test its antifungal effects.

The experimental results showed that AM-2-19 exhibited antifungal activity against over 500 pathogenic fungi. The efficacy and spectrum of AM-2-19 were overall comparable or superior to liposomal amphotericin B (AmBisome). Importantly, AM-2-19 showed activity against several strains resistant to AmBisome.

Comparison of effects in the laboratory

In summary, after more than a decade of effort, Burke and Rienstra’s team has finally decoupled the efficacy and toxicity of AmB, upgrading the last line of defense against human fungal infections to be more effective and safer.

In the future, the success of related clinical trials will undoubtedly save more lives of those infected.


About AM-2-19

 
 
AM-2-19 is a modified version of the antifungal drug Amphotericin B (AmB), developed by a research team led by Martin D. Burke and Chad M. Rienstra. This modification aimed to address the strong renal toxicity associated with AmB while maintaining or improving its antifungal efficacy.
 
 
The researchers found that AM-2-19 can kill over 500 types of fungi, demonstrating therapeutic effects comparable to or surpassing AmB. Importantly, even at maximum dosage, AM-2-19 showed no harmful effects on the kidneys, overcoming a significant limitation of the original drug.
 

The development of AM-2-19 involved a detailed analysis of AmB’s interaction with ergosterol and cholesterol at the atomic level. By adjusting a carboxylic acid group in AmB, the researchers successfully created AM-2-19, which could bind with ergosterol, extract it from fungal cell membranes, and kill the fungi. Notably, AM-2-19 did not bind with cholesterol, ensuring its improved safety profile.

The compound is currently undergoing clinical trials, and its success could mark a revolutionary advancement in antifungal treatment, offering a safer and more effective alternative to existing drugs like AmB. If approved, AM-2-19 has the potential to save lives by enhancing the treatment of fungal infections globally.


About Amphotericin B

 

Amphotericin B (AmB) is a longstanding antifungal drug first discovered in 1955. It is known for its potent antifungal properties and has been a critical component in the treatment of various systemic fungal infections. AmB is particularly effective against a broad spectrum of fungi, making it a valuable option in cases where other antifungal agents may be less successful.

The mechanism of action of Amphotericin B involves its binding to ergosterol, a key component in the fungal cell membrane. This binding disrupts the integrity of the cell membrane, forming pores that lead to increased permeability. As a result, essential cellular components leak out, ultimately causing fungal cell death. While effective, this mechanism also contributes to AmB’s side effects, including renal toxicity.

AmB has been used clinically for decades, and its historical significance lies in its ability to combat serious fungal infections. However, its use is often limited by its side effects, particularly the risk of kidney damage. Over the years, scientists have sought ways to enhance the safety profile of AmB while maintaining its efficacy.

The recent research discussed earlier focused on modifying AmB to create AM-2-19, a derivative designed to overcome the renal toxicity associated with the original drug. This modification, guided by advanced imaging techniques, has shown promising results in preclinical studies, offering a potential breakthrough in the field of antifungal treatment.

Breakthrough in Antifungal Treatment: AM-2-19 Offers Safe and Effective Alternative to Amphotericin B

References:

[1].https://www.science.org/content/article/new-antifungal-kills-without-toxic-side-effects

[2].https://medicine.illinois.edu/news/new-antifungal-molecule-kills-fungi-without-toxicity-in-human-cells-mice

[3].Maji A, Soutar CP, Zhang J, et al. Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal. Nature. doi:10.1038/s41586-023-06710-4

[4].Cavassin FB, Baú-Carneiro JL, Vilas-Boas RR, Queiroz-Telles F. Sixty years of Amphotericin B: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections. Infect Dis Ther. 2021;10(1):115-147. doi:10.1007/s40121-020-00382-7

[5].Gray KC, Palacios DS, Dailey I, et al. Amphotericin primarily kills yeast by simply binding ergosterol. Proc Natl Acad Sci U S A. 2012;109(7):2234-2239. doi:10.1073/pnas.1117280109

[6].Anderson TM, Clay MC, Cioffi AG, et al. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol. 2014;10(5):400-406. doi:10.1038/nchembio.1496

[7].Lewandowska A, Soutar CP, Greenwood AI, et al. Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes. Nat Struct Mol Biol. 2021;28(12):972-981. doi:10.1038/s41594-021-00685-4

[8].Guo X, Zhang J, Li X, et al. Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides. ACS Cent Sci. 2021;7(5):781-791. doi:10.1021/acscentsci.1c00148

(source:internet, reference only)


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