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Breaking walls: combined peptidic activities against Gram-negative human pathogens

PhD ceremony:Ms Q. Li
When:February 18, 2019
Supervisor:prof. dr. O.P. (Oscar P) Kuipers
Co-supervisor:M. Montalban -Lopez
Where:Academy building RUG
Faculty:Science and Engineering

Antibiotic resistance has become one of the biggest threats to global health and development today. The most difficult-to-treat infections are caused by Gram-negative pathogens. Nisin and vancomycin are among the most widely used antimicrobials. Nevertheless, the activity of nisin/vancomycin against Gram-negative bacteria is much lower than that against Gram-positive bacteria. The main reason is that the protective outer-membrane of Gram-negative bacteria forms an efficient barrier to prevent nisin/vancomycin to reach its target, lipid II, at the inner membrane. In order to expand spectrum and use of nisin or vancomycin to inhibit the growth of Gram-negative pathogens, two strategies were employed. One is bioengineering of nisin. Several tails with transmembrane activity were attached to various nisin moieties and the full peptides were biosynthesized in Lactococcus lactis. We found the tail can help nisin moiety to pass through the outer-membrane of Gram-negative pathogens and inhibit their growth. Another strategy is the synergism between membrane perturbing peptides and nisin and vancomycin. When combined them, the concentration of each compounds can be decreasd to 32-fold lower. It is hypothesized that the peptides can perform as a gate-opener. The best combination, which is vancomycin and GNP-D8, was proved to neither caused lysis of erythrocytes nor showed significant toxicity against the human cell line HEK-239 when tested alone or in combination. Even though further in vivo tests are needed. The fused peptides here described and combinations of two compounds constitute new and relevant therapeutic approaches to deal with (MDR) Gram-negative pathogens.