Synthetic studies with the brevicidine and laterocidine lipopeptide antibiotics including analogues with enhanced properties and in vivo efficacy

Abstract

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective...

Synthesis and structure–activity relationship studies of N-terminal analogues of the lipopeptide antibiotics brevicidine and laterocidine

“…In summary, a library of N-terminal lipid analogues was generated for brevicidine (9)(10)(11)(12)(13)(14)(15)(16)(17) and laterocidine (18-26) using our previously established synthetic approaches. The peptides were assayed in vitro against a panel of ESKAPE…”

“…8 As chiral lipids are expensive and/or must be chemically synthesized, we chose to synthesise lipid tail analogues containing cheaper, commercially available lipids. The brevicidine and laterocidine variants prepared included unacylated peptides (9 & 18) and C2-C16 lipidated brevicidine (10)(11)(12)(13)(14)(15)(16)(17) and laterocidine (19-26) analogues, with lipid length incrementally increasing by two carbons for each analogue. Peptides were synthesized in overall yields ranging between 5-27% (after HPLC purification).…”

“…The peptides were assayed in vitro against a panel of ESKAPE pathogens to identify analogues with comparable activities to synthetic brevicidine (1) and laterocidine (2). The substitution with a decanoyl tail in both brevicidine (14) and laterocidine (23) had no effect on the antimicrobial activity, including colistin-resistant E. coli. This strong activity against drugresistant Gram-negative bacteria coupled with the reduced synthetic cost highlights these analogues as potential therapeutic candidates for future development.…”

Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption

“…Absent from these prior studies, however, is an assessment of the completely mirror-image enantiomeric form of any full-length polymyxin. Such mirror-image strategies have been previously applied by our group and others to better understand the stereochemical parameters governing the mechanisms of various peptide antibiotics. − In those cases where an achiral target is implicated, the enantiomeric form of the peptide antibiotic generally exhibits activity on par with the natural product. This is the case for laspartomycin, which targets undecaprenyl phosphate (C 55 -P) as well as the clinically used bacitracin, which targets undecaprenyl pyrophosphate (C 55 -PP) .…”

“… 31 In contrast, for peptide antibiotics with an implicated chiral biomolecular target, the activity of the corresponding enantiomer is often significantly reduced. Specific examples include the recently reported laterocidine (targeting lipid A), 30 tridecaptin A1 (targeting the bacterial cell wall precursor lipid II), 29 thanatin (targeting LptA and LptD proteins involved in LPS biosynthesis), 28 and daptomycin (targeting phosphatidylglycerol). 33 In all of these examples, the antibacterial activity of the corresponding enantiomers was shown to be either severely decreased or abolished.…”