Using Marine Pharmacology in the Fight Against Drug-Resistant Infections

Antibiotic overuse and misuse to treat many infectious diseases has resulted in the development of multiple-drug-resistant pathogens. This problem is now a major threat to public health and has increased the healthcare costs associated with treating patients with drug-resistant infections. New drugs are therefore urgently needed to help combat this mounting problem.

In a review article published in The Lancet, Usama Ramadan Abdelmohsen, PhD, from the Julius-von-Sachs Institute for Biological Sciences, University of Würzburg, Germany, and colleagues discuss marine natural products (MNPs) that have shown potential against drug-resistant infections of fungal, viral, and parasitic origin.

“The marine environment has proven to be a very rich source of diverse natural products with significant antibacterial, antifungal, antiviral, antiparasitic, anti-tumour, anti-inflammatory, antioxidant, and immunomodulatory activities,” the authors write.

Antifungal Activity

Resistance to antifungal drugs has become an increasing problem, and presents a significant challenge for treatment of candidemia among immunocompromised patients, including those with AIDS.

Efflux pump-mediated resistance of Candida species to drugs such as azoles is the most common mechanism of antifungal resistance. These pumps in the fungal cell membrane reduce the drug’s activity by exporting it out of the cell, thereby reducing its concentration within the cell. One approach to overcome this resistance is to block these pumps and thus increase the activity of the antifungal drug. According to the authors, expression of fungal efflux pumps in Saccharomyces cerevisiae (which overexpresses the Candida albicans pumps) provides a system to screen for pump inhibitors.

In recent studies, a new tetramic acid glycoside known as aurantoside K was isolated from a marine sponge of the Melophlus genus. Aurantoside K showed potent antifungal activity against both wild type and amphotericin-resistant C. albicans, with no cytotoxicity in vitro against a human colon cancer cell line.

Studies have also identified a new antifungal polyketide known as forazoline A from an Actinomadura species. Forazoline A demonstrated in vivo and in vitro efficacy against C. albicans. In particular, this polyketide showed a synergistic antifungal effect with amphotericin B in vitro.

Although some natural products have no inherent antifungal activity against drug-resistant fungal infections, they may enhance the activity of azole compounds. For example, in a C. albicans multidrug resistance 1 efflux pump overexpressing Saccharomyces cerevisiae.

Antiviral Activity

MNPs have also shown potential against drug-resistant viruses, including influenza virus and HIV, the authors say.

For example, the marine-derived fungus Eurotium rubrum F33 has been found to have inhibitory effects against influenza A H1N1 virus. Further investigation of this fungus also led to identification of another compound known as neoechinulin B. This alkaloid strongly inhibited H1N1 virus in cell culture studies, and inhibited a panel of influenza clinical isolates that were resistant to several antiviral influenza drugs. It also showed no cytotoxicity against human cell lines, and additionally had markedly reduced drug-resistance-inducing properties compared with amantadine.

Sponge-associated fungi are also known to produce anti-HIV compounds. For example, Stachybotrys chartarum MXH-X73 produces stachybotrin D, which shows anti-HIV-1 activity by targeting reverse transcriptase, and without any cytotoxicity. Studies have also demonstrated that this compound has similar inhibitory effects on HIV-1 replication of wild type and several non-nucleoside reverse-transcriptase inhibitor-resistant HIV-1 strains.

Antiparasitic Activity

Novel classes of anti-malarial compounds have also been isolated from MNPs. These include marine sponges such as Haliclona species which produce haliclonacyclamine A. This compound has shown inhibitory activity in vitro against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. It also reduced mortality in Plasmodium-infected mice over an 18-day period.

Zyzzya species of marine sponges produce alkaloids such as tsitsikammamine C and makaluvamines J, G, and L. These compounds also show potent in vitro antiplasmodial activities against chloroquine-sensitive, chloroquine-resistant, and mefloquine-resistant strains of P. falciparum. Makaluvamine G has also been shown to reduce parasite growth in Plasmodium-infected mice.

Marine Actinomycetes also represent a new source of anti-malarial compounds. The marine actinomycete Salinispora tropica produces salinisporamide A which has potent inhibitory activities against chloroquine-sensitive and chloroquine-resistant clones of P. falciparum. This compound also inhibits the stages of the parasite life cycle in the red blood cell.

Salinipostins A-K have been isolated from a marine-derived Salinospora species bacterium. These compounds comprise a new class of antimalarials. In particular, salinipostin A shows the strongest inhibitory effect of the group, with no cytotoxic effects on mammalian cell lines. It also appears to be less susceptible to development of resistance.

In their concluding remarks, the authors emphasize how the diverse abundance of natural products in the marine environment holds great promise for the therapy of drug-resistant infections.

“Several MNP-based anti-infectives have already entered phase 1, 2, and 3 clinical trials, with six approved for usage by the US Food and Drug Administration and one by the [European Union],” they add.

“Development of resistance-resistant antibiotics could be achieved via the coordinated networking of clinicians, microbiologists, natural product chemists, and pharmacologists together with pharmaceutical venture capitalist companies,” the authors conclude.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.