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Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance

Although polyenes were the first broad spectrum antifungal drugs on the market, after 70 years they are still the gold standard to treat a variety of fungal infections. Polyenes such as amphotericin B have a controversial image. They are the antifungal drug class with the broadest spectrum, resistance development is still relatively rare and fungicidal properties are extensive. Yet, they come with a significant host toxicity that limits their use. Relatively recently, the mode of action of polyenes has been revised, new mechanisms of drug resistance were discovered and emergent polyene resistant species such as Candida auris entered the picture.

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 Mandimycin: A polyene antifungal with a unique mode of action

The new compound is similar in structure to amphotericin B but binds to a different target. Fungal infections may not be as common as bacterial or viral infections, but they can still be deadly. And the deadliest pathogenic fungi, such as Candida auris, are becoming increasingly resistant to approved antifungals, which is why researchers are on the hunt for new antifungal compounds. Enter a new antifungal, mandimycin. It’s the latest addition to a group of antifungals called glycosylated polyene macrolides, but it works differently from the rest. That could help it evade resistance, say its discoverers

Articles of Interest

A polyene macrolide targeting phospholipids in the fungal cell membrane

The global spread of multidrug-resistant pathogenic fungi presents a serious threat to human health, necessitating the discovery of antifungals with unique modes of action1. However, conventional activity-based screening for previously undescribed antibiotics has been hampered by the high-frequency rediscovery of known compounds and the lack of new antifungal targets. Here we report the discovery of a polyene antifungal antibiotic, mandimycin, using a phylogeny-guided natural-product discovery platform.

A safer polyene antifungal

The polyene macrolide amphotericin B (AmB) is a widely used broad-spectrum antifungal, but its use is associated with kidney toxicity. Efforts to develop renal-sparing polyene antifungals have been hindered by the belief that polyenes act by forming ion channels to permeabilize the fungal cell membrane. However, more recent studies have indicated that instead, AmB kills cells by forming large sponge-like aggregates that remove ergosterol (Erg) from the cell membrane, leading to pore formation and ion leakage.

All about polyenes

Polyenes are commonly and widely applied antifungal chemicals or drugs. They are composed of a cyclic amphiphilic macrolide substructure. They have a broad spectrum of activity that can act against a wide variety of organisms. The carbon bonds are single or double in number. They are poly-unsaturated compounds. Polyene antibiotics possess high activity against microbes, specifically fungi. The most common producer of polyene antibiotics in Streptomyces species.

Biosynthesis and pathway engineering of antifungal polyene macrolides in actinomycetes

Polyene macrolides are a large family of polyketides with potent antifungal activities. They include antibiotics such as nystatin A1, amphotericin A and B, pimaricin, candicidin/FR-008, and CE-108/rimocidin. Polyene antibiotics are structurally characterized by polyhydroxylated macrocyclic lactones comprised of 20–40 carbons with three to eight conjugated double bonds.

Management of invasive fungal infections: a role for polyenes

The armamentarium of antifungal drugs continues to grow; the three main classes of commonly administered drugs are the polyenes, azoles and echinocandins. The newer triazoles and the echinocandins have changed primary treatment options for some fungal infections, such as aspergillosis and candidiasis. However, despite their toxic potential, the oldest antifungal drugs, polyenes, remain useful in the treatment of IFIs because of their broad-spectrum activity, low rates of resistance and established clinical record, particularly in immunocompromised patients with breakthrough fungal infections.

Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications

The phenomenon of the interaction of polyenes with the lipid membrane has been studied for decades. Polyenes are quite small molecules, for biological standards, but present a wide variety of phenomena depending on concentration, solvent, pH , oxidation, and membrane properties.

Polyenes

Typically derived from the fermentation products of Streptomyces bacteria, polyene antifungals bind to ergosterol in the fungal cell membrane, allowing K+ and Na+ ions to leak out. Amphotericin B is often used for serious fungal infections and has earned the nickname ‘amphoterrible’ for its unpleasant side effects.

Structure-Antifungal Activity Relationships of Polyene Antibiotics of the Amphotericin B Group

Despite the relatively recent introduction of new antifungal drug such as next-generation azoles and echinocandins, polyene macrolides continue to be the most potent broad-spectrum antifungals available for the clinical use. Amphotericin B (AMB; compound is the drug of choice for the treatment of mycotic infections caused by a wide range of fungi.

The Multifaceted Polyenes–They Are Everywhere

The polyene molecule is easily recognized as a chain of carbon atoms, which have alternating double and single bonds, and various groups of atoms attached at either end. But this simple explanation belies their complexity. Polyenes and their derivatives are found everywhere in living organisms: bacteria, archaea, plants, animals, and humans. In a 2013 article, Buckup and Motzkus call biopolyenes “the all-around Swiss army knife of nature.” One common subset of compounds with a polyene backbone is the carotenoids. A very famous carotenoid is beta-carotene, as it is a pigment that imparts vibrant color to carrots (which indeed influenced the moniker “carotenoid”).

Unearthing the story of the first antifungal drugs

The serendipitous discovery of early antibiotics from a fateful contaminating fungus in Alexander Fleming’s laboratory is one of the most celebrated and recounted tales among microbiologists. Yet few among us know the history behind the discovery of the first antifungal drug by two pioneering women, Elizabeth Hazen and Rachel Brown, whose names and legacy have been largely overlooked, yet whose discovery remains fundamentally important today. Indeed, as human fungal disease becomes increasingly widespread and new fungal pathogens emerge due to a dangerous confluence of increasingly vulnerable populations and climate change, lifesaving antifungal therapies are of greater consequence than ever before.

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Doctor Fungus

These very potent agents act by binding to the fungal cell membrane and causing the fungus to leak electrolytes.