Abstract
NZ2114 is a promising candidate for therapeutic application owing to its potent activity to Staphylococcus aureus. Our objective was to identify NZ2114 derivatives with improved activity through substitution of His16 and His18 with residues Arginine and Lysine. Eight mutants were designed and expressed in Pichia pastoris X-33 via pPICZαA. Five of them exhibited strong antimicrobial activity against S. aureus at low minimal inhibitory concentrations (MICs) of 0.057–0.454 μM. Among them, H1, H2, and H3 showed ideal pharmacodynamic effects on methicillin-resistant S. aureus ATCC43300. The total protein level of H1, H2, and H3 reached 1.70, 1.77 and 1.54 g/l at 120 h of induction in the 5-l fermenter, respectively. They killed over 99.9% of pathogens within 1.5 h at 2× and 4× MIC. The post antibiotic effect of H1, H2 and H3 to S. aureus ATCC43300 was 2.94, 1.75 and 1.55 h at 2× MIC, which was similar with their original peptide NZ2114 (1.43 h) and vancomycin (1.72 h). The fractional inhibitory concentration index (FICI) indicated indifferent effects between H1, H2, H3 and vancomycin, ampicillin, rifampicin. Additionally, they had low hemolysis and high stability in different environments (temperature, pH, proteases, and saline ions). All results indicate that H1, H2, and H3 can be produced in large-scale and have potential as therapeutic drugs against MRSA.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common antimicrobial-resistant pathogens causing invasive infections (Dantes et al 2013), which can produce a series of toxins and shows frequent and sometimes multi-drug resistance to antimicrobials (Stefani et al 2012)
Data from the tigecycline evaluation and surveillance trial showed that proportion of MRSA with minimal inhibitory concentration (MIC) ≥2 mg/l increased from 5.6% in 2004 to 11.1% in 2009 (P < 0.001) (Hawser et al 2011)
Three peptides all Discussion Currently, 2764 anitimicrobial peptide (AMP) are registered in the antimicrobial peptide database (APD)
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common antimicrobial-resistant pathogens causing invasive infections (Dantes et al 2013), which can produce a series of toxins and shows frequent and sometimes multi-drug resistance to antimicrobials (Stefani et al 2012). Peptide NZ2114 is a novel variant of plectasin (D9N, M13L, Q14R) that is significantly more potent than parental peptide (MIC50: 2 μg/ml for S. aureus and 0.25 μg/ml for S. pneumoniae) (Ostergaard et al 2009; Zhang et al 2014; Andes et al 2009; Xiong et al 2011) It had long postantibiotic effect (PAE) (Zhang et al 2014) and synergistic in combination with the conventionl antibiotics such as teicoplanin, moenomycin, and dalbavancin (Breidenstein et al 2015). It had potent activities against S. aureus in rabbit meningitis, murine peritonitis, and thigh infection models (Ostergaard et al 2009; Andes et al 2009; Xiong et al 2011). NZ2114 showed low or no cell toxicities, long-lasting serum stability and in vivo half-life (Brinch et al 2010)
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