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Streptomyces: A Potential Source of Natural Antimicrobial Drug Leads
Published in Mahendra Rai, Chistiane M. Feitosa, Eco-Friendly Biobased Products Used in Microbial Diseases, 2022
Mahmoud A. Elfaky, Hanaa Nasr, Ilham Touiss, Mohamed L. Ashour
One of the rational engineering approaches is to manipulate regulatory genes genetically. Overexpression of the pathway-specific regulatory gene sanG, for example, resulted in a significant increase in nikkomycin production. More recently, evidence has emerged that Streptomyces signaling mechanisms are critical for secondary metabolite biosynthesis. Overexpression of the -butyrolactone signaling molecule synthase gene afsA-gR in Streptomyces fradiae resulted in a 1.7-fold rise in neomycin development compared to the wild form (Li et al. 2019).
Caspofungin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Russell E. Lewis, Nicholas D. Beyda, Dimitrios P. Kontoyiannis
Other nonconventional antifungals have also been reported to be effective against Aspergillus species when tested in combination with echinocandins. Combinations of calcineurin inhibitors or rapamycin with caspofungin demonstrates synergistic effects (Kontoyiannis, Lewis et al., 2003). The combined use of nikkomycin Z (a chitin synthesis inhibitor) markedly enhanced the lethality of echinocandins against Aspergillus species in vitro (Ganesan et al., 2004).
Infections and infestations affecting the nail
Published in Eckart Haneke, Histopathology of the NailOnychopathology, 2017
Coccidioidomycosis is a systemic mycosis due to the dimorphic fungus Coccidiodes immitis, less frequently C. posadasii. It results from inhalation of the fungus and may remain asymptomatic, or run a benign, a serious, or a fatal course. It affects immunocompetent as well as immunocompromised subjects as a primary pathogen or an opportunistic agent, respectively. Most cases are seen in California, Arizona, and bordering Mexico with 60% remaining asymptomatic. All persons living or travelling to endemic areas are exposed. Many animals including cats and dogs are infected.268 All ages and both sexes are affected. In severe cases of disseminated coccidioidomycosis, bones and joints may be involved and thus nail unit and skin lesions secondarily occur in 15%–20% of the cases.269 Primary skin infection is very rare, mostly resulting from accidental inoculation in laboratories or autopsy rooms,270,271 rarely as infection resulting from an injury by a thorn or splinter.272,273 One to three weeks after the inoculation, a tender nodule forms that enlarges to a plaque and ulcerates. Regional lymphangitis and lymphadenitis follow. Healing takes several months. The coccidioidin test aids in making, or confirming, the diagnosis. Treatment of severe cases is with intravenous amphotericin B, which is a relatively toxic regimen. Alternatives are posaconazole, ketoconazole, and the triazoles itraconazole and fluconazole. Trials have been performed with nikkomycin Z, which inhibits chitin synthetase, caspofungin, and voriconazole.
Existing and emerging therapies for the treatment of invasive candidiasis and candidemia
Published in Expert Opinion on Emerging Drugs, 2022
David De Bels, Evelyne Maillart, Françoise Van Bambeke, Sebastien Redant, Patrick M. Honoré
The last class of antifungals acting on a new target in Candida are polyoxins, with nikkomycin being the only drug under clinical development since more than 15 years, asking question about its potential future. It is a competitive inhibitor of chitin synthase, an essential structural component of fungal cell walls [95]. It shows fungicidal activity against endemic dimorphic fungi, including Coccidiosis’s, Histoplasma, and Blastomyces spp, but inconstant activity against other fungi, with MIC ranging from 0.125 to >64 mg/L. MIC50 and MIC90 are respectively 2 and 32 mg/L for C. auris [96]. Nikkomycin it thus mainly used in combination with amphotericin B, azoles, or echinocandins, allowing to observe synergistic effects against a range of medically important fungi [97,98]. The first three phase 1 trials have been only recently completed. Drug dosage were tested between 50 mg BID to 750 mg TID or ones orally between 250 mg to 2,000 mg [99].
The antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy
Published in Expert Review of Anti-infective Therapy, 2022
Shan Su, Haiying Yan, Li Min, Hongmei Wang, Xueqi Chen, Jinyi Shi, Shujuan Sun
Nikkomycin Z, which is undergoing a clinical trial for treating fungal infections, is a specific chitin synthase inhibitor. A recent study demonstrated the combined antifungal effects of Nikkomycin Z and caspofungin against Saccharomyces cerevisiae (S. cerevisiae) (WT BY4741). The MIC of Nikkomycin Z was reduced from 12.5 µg/mL to 3.125 µg/mL, the MIC of caspofungin was reduced from 0.03 µg/mL to 0.00625 µg/mL, and the FICI was 0.4583 [50]. Another study demonstrated that the combination of caspofungin and nikkomycin Z caused extended cell death and that the structure of the biofilm was sparse compared to the control. This drug combination showed synergistic effects against three of five total caspofungin-susceptible C. albicans isolates (n = 5, there were five isolates in total) and one caspofungin-resistant C. albicans isolate [51]. Two new potential antifungal compounds, IMB-D10 and IMB-F4, were isolated based on a chemical genetic method. They inhibited the activity of chitin synthase in vitro and reduced chitin levels in yeast cells. The antifungal effects of caspofungin were detected, and IMB-F4 exhibited excellent activity with FICI < 0.5 [50].
Repurposing of Streptomyces antibiotics as adenosine deaminase inhibitors by pharmacophore modeling, docking, molecular dynamics, and in vitro studies
Published in Journal of Receptors and Signal Transduction, 2020
K. G. Arun, C. S. Sharanya, J. Abhithaj, C. Sadasivan
The selected antibiotics that showed high fitness with the pharmacophore were selected, and docking studies were conducted. From the high scoring compounds, based on commercial availability, two compounds namely, nikkomycin Z and novobiocin, were selected for in vitro studies. nikkomycin Z is a nucleoside-peptide antibiotic produced by Streptomyces species with antifungal activities through the inhibition of chitin synthesis. The pharmacophore-based virtual screening studies revealed nikkomycin Z has good fitness with the pharmacophore model. The fitness score obtained was 1.25 (Figure 4). Binding score obtained from docking study was –12.78 Kcal/mol (Table 3). The bound compound was stabilized by hydrogen bonds with protein residues (Asp 16, Leu 53, Gly 181, Glu 183, and Glu 214) and pi-pi stacking interaction (His 14) (Figure 5(a)). The second compound Novobiocin, an aminocoumarin antibiotic from Streptomyces species, showed tight binding with ADA active site. The compound showed excellent fitness with the generated pharmacophore (fitness score 1.96) (Figure 4), and docking score was found as –7.27 Kcal/mol. Novobiocin interacted with ADA active site through hydrogen bonding with protein residues Asp 63, Asn 115, and Asp 292 and pi-pi interaction with His 14 (Figure 5(b)).