Semisynthetic Lipopeptides Derived from Nisin Display Antibacterial Activity and Lipid II Binding on Par with That of the Parent Compound

Abstract

The lipid II-binding N-terminus of nisin, comprising the so-called A/B ring system, was synthetically modified to provide antibacterially active and proteolytically stable derivatives. A variety of lipids were coupled to the C-terminus of the nisin A/B ring system to generate semisynthetic constructs that display potent inhibition of bacterial growth, with activities approaching that of nisin itself. Most notable was the activity observed against clinically relevant bacterial strains including MRSA and VRE. Experiments with membrane models indicate that these constructs operate via a lipid II-mediated mode of action without causing pore formation. A lipid II-dependent mechanism of action is further supported by antagonization assays wherein the addition of lipid II was found to effectively block the antibacterial activity of the nisin-derived lipopeptides.

Catalytic Modification of Dehydroalanine in Peptides and Proteins by Palladium‐Mediated Cross‐Coupling

“…Moreover, conjugate addition of water to Dha, and hydrolytic cleavage at this site are known degradation reactions . Despite the potential of Nisin as an antibiotic, to the best of our knowledge, no catalytic methods for modification have been reported, and stoichiometric chemical modifications are scarce …”

Bioorthogonal Metalloporphyrin‐Catalyzed Selective Methionine Alkylation in the Lanthipeptide Nisin

“…Selective chemical modification of RiPPs offers the possibility of further improving their properties and/or activity. A plethora of selective, bioorthogonal reactions for the modification of specific amino acid residues in proteins and peptides have been developed, some of which have been applied to RiPPs . However, methods for selective methionine modification are rare .…”

New Found Hope for Antibiotic Discovery: Lipid II Inhibitors

“…However, rings A–B are inactive on their own . It is suggested that upon pyrophosphate cage formation, the rings C–E (C‐terminus) of nisin insert into the lipid bilayer, thereby facilitating the assembly of nisin‐lipid II pore complex which leads to the lysis of bacteria . This dual mechanism‐of‐action makes nisin a very potent Gram‐positive antibacterial agent.…”

“…Semisynthetic analogues have been developed whereby the C–E domain of the natural product was replaced with various lipid substituents. Several of these derivatives that showed enhanced proteolytic stability and potent antibacterial activity hold great therapeutic promise …”