Antimicrobial peptides are considered promising candidates for the development of novel antimicrobial agents to combat infections by multi-drug-resistant (MDR) bacteria. Here, we describe the... Show moreAntimicrobial peptides are considered promising candidates for the development of novel antimicrobial agents to combat infections by multi-drug-resistant (MDR) bacteria. Here, we describe the identification and characterization of the synthetic peptide TC19, derived from the human thrombocidin-l-derived peptide L3. Biophysical experiments into the interaction between TC19 and mimics of human and bacterial plasma membranes demonstrated that the peptide is highly selective for bacterial membranes. In agreement, TC19 combined low cytotoxicity towards human fibroblasts with efficient and rapid killing in human plasma of MDR strains of several bacterial species of the ESKAPE panel. In addition, TC19 induced minor resistance in vitro, neutralized pro-inflammatory activity of bacterial cell envelope components while displaying slight chemotactic activity for human neutrophils. Importantly, topical application of TC19-containing hypromellose gel significantly reduced numbers of viable methicillin-resistant Staphylococcus aureus (MRSA) and MDR Acinetobacter baumannii in a superficial wound infection in mice. Together, TC19 is an attractive candidate for further development as a novel agent against (MDR) bacterial skin wound infections. Show less
Breij, A. de; Riool, M.; Cordfunke, R.A.; Malanovic, N.; Boer, L. de; Koning, R.I.; ... ; Nibbering, P.H. 2018
This study aimed to identify compounds that enhance the activity of current antibiotics against multidrug-resistant bacteria. Screening of a 350+ compound proprietary small molecules library... Show moreThis study aimed to identify compounds that enhance the activity of current antibiotics against multidrug-resistant bacteria. Screening of a 350+ compound proprietary small molecules library revealed that the Glycyrrhiza glabra (licorice)-derived triterpenoid 18 beta-glycyrrhetinic acid (18 beta-GA) potentiated the antibacterial activity of certain antibiotics against Staphylococcus aureus. Here, we evaluated the ability of pentacyclic triterpenoids to potentiate the activity of antibiotics against strains of methicillin-resistant S. aureus (MRSA). Checkerboard assays were used to assess the minimum inhibitory concentration (MIC) of tobramycin and ten pentacyclic triterpenoids against S. aureus. The effect of 18 beta-GA on the MIC of different antibiotics against MRSA was also determined in an in vitro airway MRSA infection model. 18 beta-GA enhanced the bactericidal activity of the aminoglycosides tobramycin, gentamicin and amikacin, and of polymyxin B against two MRSA strains, reducing the MIC of these antibiotics 32-64-fold [fractional inhibitory concentration index (FICI) of 0.12-0.13]. Other beta-amyrin triterpenoids and alpha-amyrin triterpenoids did not exert such synergistic effects. 18 beta-GA did not enhance the activity of antibiotics from other structural classes against the MRSA strains. In an air-exposed airway epithelial cell culture, 18 beta-GA enhanced the bactericidal activity of tobramycin and polymyxin B against the MRSA strain. These data demonstrate the potential of 18 beta-GA to synergise with certain types of antibiotics to eliminate strains of MRSA. Show less
Breij, A. de; Riool, M.; Kwakman, P.H.S.; Boer, L. de; Cordfunke, R.A.; Drijfhout, J.W.; ... ; Moriarty, T.F. 2016
Background: The dramatic increase in antibiotic resistance and the recent manifestation in war trauma patients underscore the threat of Acinetobacter baumannii as a nosocomial pathogen. Despite... Show moreBackground: The dramatic increase in antibiotic resistance and the recent manifestation in war trauma patients underscore the threat of Acinetobacter baumannii as a nosocomial pathogen. Despite numerous reports documenting its epidemicity, little is known about the pathogenicity of A. baumannii. The aim of this study was to obtain insight into the factors that might explain the clinical success of A. baumannii. Methodology/Principal Findings: We compared biofilm formation, adherence to and inflammatory cytokine induction by human cells for a large panel of well-described strains of A. baumannii and compared these features to that of other, clinically less relevant Acinetobacter species. Results revealed that biofilm formation and adherence to airway epithelial cells varied widely within the various species, but did not differ among the species. However, airway epithelial cells and cultured human macrophages produced significantly less inflammatory cytokines upon exposure to A. baumannii strains than to strains of A. junii, a species infrequently causing infection. Conclusion/Significance: The induction of a weak inflammatory response may provide a clue to the persistence of A. baumannii in patients. Show less
