| Stable conformational constraints, such as thioether- or disulfide bridges, are essential for the biological activity of peptides. Replacement of these natural constraints by synthetic isosteres has recently received much attention in our group.1 Such synthetic constraints not only shed light on structure-activity relationships but also can generate variants that display better metabolic stability. In this regard, nisin (A. Chart 1) has been chosen as a model compound. An example of such a synthetic isostere is an alkene- or alkyne bridge which can be incorporated in peptides by ring-closing metathesis (RCM) or ring-closing alkyne metathesis (RCAM), respectively. Both metathesis reactions display an extraordinary functional group tolerance and high yield of cyclization which emphasize their versatility to introduce alkene/alkyne-based conformational constraints into peptides.2,3 Nisin belongs to the lantibiotics, a natural class of antimicrobial peptides.4,5 Nisin binds via its N-terminus, comprising the AB(C)-ring system, to lipid II, which is an essential precursor for cell wall biosynthesis (B. Chart 1). As a result, the C-terminus, comprising the knotted DE-ring, can form pores in the phospholipid membrane which ultimately results in cell leakage and causes a collapse of the vital ion gradients across the membrane.6 This unique binding target and mode of action makes nisin and its fragments an attractive lead compound for the development of novel peptide-based antibiotics.7 Recently, we communicated the syntheses and binding affinity toward lipid II of alkene/alkyne-bridged nisin AB-, ABC- and DE-ring mimics.1g-h,8-11 Chart 1 The aim of this research proposal is the design and synthesis of new hybrid peptide antibiotics based on the unique mechanism of action of nisin. The assembly of a semi-synthetic nisin molecule is realized by the combination of, for example, a native AB-fragment (obtained by enzymatic digestion) with a synthetic alkene-bridged DE-ring mimic, linked together via a suitable spacer (C. Chart 1). These molecular constructs display a dual mode of action: firstly, the AB-ring ensures high binding affinity toward lipid II which is on itself bacteriostatic5c and secondly, depending on the spacer/DE-ring moiety, pore formation can occur, thereby disrupting the vital ion gradients in the cell. These newly designed molecules offer opportunities to tune the desired mode of action which can be used to increase specificity and decrease unspecific toxicity. |
