MOLIFE RESEARCH SEMINAR: PROF. DR. MIGUEL VINAS

MoLife Research Seminar by;

Prof. Dr. Miguel Vinas, Medical School, University of Barcelona, Spain

Title of the talk:

Bioinspired synthetic peptides and old antibiotics can help us in fighting multidrug resistant bacteria

The increasing frequency of isolation of multidrug-resistant bacteria (particularly Gram negative such as P. aeruginosa is a major cause of concern. Antimicrobial resistance in these organisms is mostly due to three well-known basic mechanisms: uptake and efflux balance, target modifications and inactivation of the drug. Carbapenems, and particularly imipenem, are broad-spectrum antimicrobials being commonly used for the treatment of MDR infections. Their mechanism of action is based in the inhibition of the third step of the synthesis of bacterial cell wall by binding to certain penicillin-binding proteins (PBPs). Imipenem is active against a wide variety of microorganisms, both Gram-negative (P. aeruginosa, Acinetobacter spp.) and Gram-positive (Streptococcus pneumoniae and Enterococcus faecalis). The use of this antimicrobial is restricted to severe infections where microorganisms have acquired resistance to other drugs. Imipenem-resistant isolates have emerged in the last few years. The main mechanism of resistance to imipenem in P. aeruginosa is the loss or the alteration of the OprD porin. The emergence of multidrug-resistant gram-negative bacteria, as well as the lack of new drugs to combat them, has stimulated the rescue of polymyxins as therapeutic options. Colistin like other cationic polypeptides is an amphipathic compound. It is believed that this amphipathic nature is relevant for its activity against bacteria. The hydrophilic part, positively charged, would interact with the bacterial negatively charged outer membrane. By this way the hydrophobic part of the polypeptide would be allowed to entry through the bacterial cytoplasmic membrane. Another mechanism proposed is the interaction with binding sites of divalent cations such as Mg²⁺ and Ca²⁺; this competitive binding would disturb the properties and stability of the outer membrane. Ultimately, bacterial death would be due to the insertion of the peptide into the cytoplasmic membrane forming channels, where small molecules and ions and even proteins would pass; and that also can eventually be used as a way to penetrate bacteria by other antimicrobial agents. The exploration of antimicrobial peptides (AMP) mimicking the structure and mechanism of action of polymixins can be regarded as a main goal of this field of research. Such synthetic AMPs would allow opening perspectives in order to reduce secondary effects and enhance antimicrobial action.

Synthesis of safe and effective antimicrobial peptides in the laboratory could open new frontiers to combat multidrug resistance. An unlimited number of new molecules with antimicrobial activity could be designed. The challenge lies behind finding new molecules with higher activity and lower toxicity than conventional known drugs. 

We have explore the antimicrobial activity of a novel synthetic cyclolipopeptide analog of polymyxin (AMP38) and its synergy with imipenem to improve treatment for infections caused by imipenem-resistant P. aeruginosa. AMP38  . The aim was to explore the antimicrobial activity of a synthetic peptide (AMP38) and its synergy with imipenem against imipenem-resistant P. aeruginosa. The main mechanism of imipenem resistance is the loss or alteration of protein OprD. Time-kill and eradication biofilm (MBEC) determinations in a clinical imipenem-resistant strain demonstrate that AMP38 was markedly synergistic with imipenem when determined in imipenem –resistant P. aeruginosa. MBEC obtained for the combination of AMP38 and imipenem was of 62.5 µg/ml whereas MBEC of each of antimicrobials separately is 500 µg/ml.  AMP-38 should be regarded as a promising antimicrobial to fight MDR P. aeruginosa infections. Moreover, killing effect and antibiofilm activity of AMP38 plus imipenem is much higher than that of colistin plus imipenem.

Further information by the host Prof. Dr. Roland Benz, Professor of Biotechnology,Email: r.benz@jacobs-university.de,  Focus Area: Health - Life Sciences & Chemistry, Tel: +49 421 200-3151, Link to Homepage: https://www.jacobs-university.de/ses/rbenz