Nikkomycins Are Finally Getting Some Respect

Besides azoles, candins and the polyene class of antifungals there is not much to select from when it comes to systemic fungal infections.  Until the recent arrival of voriconazole and posaconazole, infections caused by molds always required amphotericin B to control.  Only for Candida several good treatments exist on the market, the fungistatic azoles and the fungicidal candins.

For the endemic mycoses (histo, cocci, blasto) treatment options are still rather limited.  Itraconazole remains a useful drug for severe or progressive forms of histo but the best therapeutic approach for cocci is less clear.  In the absence of solid data supporting a specific antifungal or class, azoles, candins and amphotericin are all potential agents to be tried sequentially.[1]  There is no truly curative therapy as of yet and many patients relapse even after prolonged courses of therapy.  Cocci meningitis is a dreaded disease which is practically untreatable.Nikkomycin structure

The nikkomycins could fill this gap. Nikkomycins are peptide-nucleoside drugs that act as chitin synthase inhibitors. Despite this new mode of action, impressive fungicidal activity and a good safety record in early clinical trials, they have not attracted much attention or funding.  This lack of interest by Big Pharma is clearly related to NikZ’s narrow spectrum which is confined to cocci and blasto.

A group of researchers/clinicians with a long track record in this field are now taking matters into their own hands.  With the help of the Univ. of Arizona, they formed Valley Fever Solutions, Inc. with the single-minded goal of developing NikZ as an orphan drug for cocci.  Of note, on Oct. 7, 2014, NikZ received QIDP status and Fast Track designation from FDA.ValleyFeverSolutions

As already mentioned, nikkomycins are chitin synthase inhibitors.  Despite the fact that chitin is part of the most fungal cell walls, the activity spectrum is narrow.  Here a short summary of the antifungal spectrum based on animal (murine) data:

  1. Coccidioidomycosis: This is the primary intended use for nikkomycins. Seminal studies conducted by Richard Hector at Bayer showed that nikkomycins can convert a mortality rate of 100% into a survival rate of 100%.[2]
  2. Blastomycosis: Studies by Clemons showed that nikkomycin is more active than itraconazole and probably equipotent (at high doses) to amphotericin B.[3]
  3. Histoplasmosis: There seems to be at least partial activity against Histoplasma. In a murine model, nikkomycin prevented mortality and reduced pulmonary fungal CFU/g in tissue (the latter not as much as treatment with itraconazole or amphotericin).[4]
  4. Cryptococcus: There are few studies addressing the activity of nikkomycins against this pathogen.  Combination therapy with azoles provided additive / synergistic activity.[5]
  5. Candida sp.: Although the chitin synthase in Candida is very prone to inhibition by nikkomycin, NikZ has little activity against intact fungal cells.   Candida are not susceptible to nikkomycin monotherapy but combination therapy with azoles may provide additive / synergistic activity 6
  6. Aspergillus sp.: In the mouse model, Nikkomycin monotherapy  was ineffective, however, when combined with the candin micafungin survival was significantly improved.[6]

In summary, there is good to excellent animal efficacy data for cocci and blasto. Future clinical data will clarify the usefulness of NikZ in man and in these and other fungal infections.  There is great need for better therapies and more treatment options for patients with Valley Fever. So far, it looks like NikZ could fill this gap.

References:

[1] http://emedicine.medscape.com/article/215978-overview
[2] R Hector AAC 34: 587, 1990
[3] K Clemons  AAC 41: 2026, 1997
[4] J Goldberg.  AAC 44:1624 2000
[5] R Li.  AAC 43:1401, 1999
[6] K Clemons.  Med Mycol. 2006 44:69, 2006

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