In Vitro Antifungal Activity of Nikkomycin Z in Combination with Fluconazole or Itraconazole

Abstract

Nikkomycins are nucleoside-peptide antibiotics produced byStreptomyces species with antifungal activities through the inhibition of chitin synthesis. We investigated the antifungal activities of nikkomycin Z alone and in combination with fluconazole and itraconazole. Checkerboard synergy studies were carried out by a macrobroth dilution procedure with RPMI 1640 medium at pH 6.0. At least 10 strains of the following fungi were tested: Candida albicans, other Candida spp., Cryptococcus neoformans, Coccidioides immitis,Aspergillus spp., and dematiacious fungi (includingExophiala jeanselmei, Exophiala spinifera,Bipolaris spicifera, Wangiella dermatitidis,Ochroconis humicola, Phaeoannellomyces werneckii, and Cladophialophora bantiana), and 2 strains each of Fusarium, Scedosporium,Paecilomyces, Penicillium, andTrichoderma spp. A total of 110 isolates were examined. Inocula of fungal elements were standardized by hemacytometer counting or spectrophotometrically. MICs and minimum lethal concentrations (MLCs) were determined visually by comparison of growth in drug-treated tubes with growth in drug-free control tubes. Additive and synergistic interactions between nikkomycin and either fluconazole or itraconazole were observed against C. albicans, Candida parapsilosis, Cryptococcus neoformans, andCoccidioides immitis. Marked synergism was also observed between nikkomycin and itraconazole against Aspergillus fumigatus and Aspergillus flavus. No antagonistic interaction between the drugs was observed with any of the strains tested.

Scedosporium apiospermum: changing clinical spectrum of a therapy-refractory opportunist*

“…However, these results must be interpreted with caution because recently the criteria for evaluating interactions have changed and FICI values over 0.5 are now considered to be indicative of no synergy [123]. Li and Rinaldi [124] demonstrated that the combination of the nucleoside-peptide antibiotic nikkomycin Z, which is a chitin synthase inhibitor, with ITC resulted in moderate in vitro growth inhibition of Scedosporium spp. The combination AMB/micafungin (MFG) shows in vitro synergistic effect against S. apiospermum [125].…”

Review of Newer Antifungal and Immunomodulatory Strategies for Invasive Aspergillosis

“…The naturally occurring nikkomycins are nucleoside-peptide antibiotics that inhibit the synthesis of cell wall chitin, a polysaccharide found in most fungi but not in mammalian cells, as competitive analogues of the substrate UDP-N-acetylglucosamine for the enzyme chitin synthase [14,27]. The effect is analogous to the action of the b-lactam antibiotics on bacteria cell walls, leading to osmotic lysis [28]. Nikkomycins were first described as a class of drugs in 1976, isolated as a result of a program to discover fungicides for agricultural use [29].…”

“…Nikkomycins were first described as a class of drugs in 1976, isolated as a result of a program to discover fungicides for agricultural use [29]. The antifungal activity of nikkomycin Z against opportunistic fungi has been reportedly low in many experimental fungal models, including ineffective growth inhibition against Aspergillus fumigatus [28,[30][31][32], leaving combination therapy as a potential option.…”

Identification of a novel antifungal nonapeptide generated by combinatorial approach

“…Synergic activity of various compounds against fungi has been reported by many workers [9]. Theoretically, the simultaneous administration of polyenes and imidazoles should result in antagonism because these drugs exert their action either directly on ergosterol or enzymes involved in its synthesis.…”