Zhuo Shang, PhD’s discovery of mandimycin offers a potential solution to drug-resistant infections like Candida auris by targeting phospholipids in fungal membranes.
The rising prevalence of multidrug-resistant fungal pathogens has posed a challenge to medical treatment, emphasizing the need for antifungal agents with novel mechanisms of action. Traditional antifungal drugs, such as amphotericin B, have been used for decades but are becoming less effective due to the emergence of resistant strains like Candida auris. Conventional activity-based screening methods for new antibiotics often fall short due to the high rate of rediscovery of known compounds and the lack of new antifungal targets. A discovery has shed light on a solution: mandimycin, a polyene antifungal antibiotic with a unique mode of action.
Zhuo Shang, PhD, a researcher at the School of Pharmaceutical Sciences, Shandong University, in collaboration with Zongqiang Wang’s, PhD, group at China Pharmaceutical University, identified mandimycin using a phylogeny-guided natural product discovery platform. This approach analyzes the evolutionary relationships of microorganisms to identify compounds, leading to the identification of mandimycin as a new polyene antibiotic with structural differences from previously known polyene macrolides. Specifically, mandimycin is biosynthesized by the mand gene cluster and incorporates three deoxy sugars, making it structurally distinct.
In contrast to traditional polyene macrolides, such as amphotericin B, which exert antifungal effects by targeting ergosterol, a key component of fungal cell membranes, mandimycin has a different mechanism. "Traditional polyene macrolides, with amphotericin B as the most well-known representative, exert their antifungal activity by binding to ergosterol, a key component of fungal cell membranes, ultimately disrupting membrane integrity and leading to cell death," said Shang. While amphotericin B has been widely used to treat fungal infections, the emergence of resistant strains, particularly Candida auris, has limited its effectiveness. Resistant strains have developed mechanisms to evade the fungicidal effects of amphotericin B, resulting in reduced clinical outcomes.
Mandimycin targets phospholipids in the fungal cell membrane rather than ergosterol, marking a crucial difference in its mode of action. "Mandimycin, in contrast, employs a novel mode of action by targeting phospholipids in fungal cell membranes rather than ergosterol," Shang explained. This interaction leads to the release of essential ions from fungal cells, resulting in membrane damage and eventual cell death. Mandimycin's ability to target multiple phospholipids sets it apart from traditional polyene macrolides, which bind to a single target, ergosterol. By binding to various phospholipids, mandimycin reduces the likelihood of resistance development, an issue that has been a significant challenge for current antifungal treatments.
Mandimycin targets phospholipids in fungal cell membranes, unlike traditional polyene macrolides that target ergosterol.
The drug demonstrates activity against multidrug-resistant pathogens such as Candida auris.
Mandimycin evades resistance mechanisms, offering potential for treating emerging multidrug-resistant fungal infections, with safety concerns still needing resolution.
In preclinical studies, mandimycin has shown broad-spectrum fungicidal activity against a range of multidrug-resistant fungal pathogens, including those listed in the WHO Fungal Priority Pathogens List. Notably, it demonstrated strong efficacy against Candida auris, a difficult-to-treat pathogen with limited treatment options. Shang remarked, "Our study demonstrated that mandimycin is highly effective against various multidrug-resistant fungal pathogens listed in the WHO Fungal Priority Pathogens List, both in cell-based assays and mouse infection models. Notably, it shows strong activity against multidrug-resistant Candida auris, a notoriously difficult-to-treat pathogen with limited treatment options."
This makes mandimycin a candidate for addressing the growing threat of multidrug-resistant fungal infections. Its ability to evade resistance mechanisms commonly encountered with other antifungal agents, such as amphotericin B, could represent a breakthrough in the fight against these infections.
Shang also acknowledged the challenges that remain in developing mandimycin for clinical use. "In the next steps, we plan to thoroughly evaluate mandimycin's safety and efficacy using additional animal models. While mandimycin has demonstrated lower renal toxicity compared to amphotericin B, its ability to bind multiple phospholipids raises potential concerns about off-target toxicity, as all cell membranes consist of a phospholipid bilayer," he noted. Addressing these safety concerns will be crucial before mandimycin can be brought to market.
Mandimycin's discovery through the phylogeny-guided natural-product discovery platform represents an advancement in the search for antifungal agents with distinct mechanisms of action. The compound’s ability to target multiple phospholipids in fungal membranes and evade resistance mechanisms offers new hope in treating multidrug-resistant fungal infections. As research and development progress, mandimycin could become a tool in combating fungal pathogens that are increasingly resistant to existing treatments.
