The Lipopeptide Antibiotic Friulimicin B Inhibits Cell Wall Biosynthesis through Complex Formation with Bactoprenol Phosphate

Abstract

Friulimicin B is a naturally occurring cyclic lipopeptide, produced by the actinomycete Actinoplanes friuliensis, with excellent activity against gram-positive pathogens, including multidrug-resistant strains. It consists of a macrocyclic decapeptide core and a lipid tail, interlinked by an exocyclic amino acid. Friulimicin is water soluble and amphiphilic, with an overall negative charge. Amphiphilicity is enhanced in the presence of Ca 2؉ , which is also indispensable for antimicrobial activity. Friulimicin shares these physicochemical properties with daptomycin, which is suggested to kill gram-positive bacteria through the formation of pores in the cytoplasmic membrane. In spite of the fact that friulimicin shares features of structure and potency with daptomycin, we found that friulimicin has a unique mode of action and severely affects the cell envelope of gram-positive bacteria, acting via a defined target. We found friulimicin to interrupt the cell wall precursor cycle through the formation of a Ca 2؉ -dependent complex with the bactoprenol phosphate carrier C 55 -P, which is not targeted by any other antibiotic in use. Since C 55 -P also serves as a carrier in teichoic acid biosynthesis and capsule formation, it is likely that friulimicin blocks multiple pathways that are essential for a functional gram-positive cell envelope.

The action mechanism of daptomycin

“…The members of this group also share one action mechanism, which consists of binding and sequestering undecaprenol phosphate, a bacterial membrane constituent that is an essential carrier coenzyme in the assembly and membrane translocation of peptidoglycan precursors. This was shown first for amphomycin 28,29 and more recently for friulimycin 30 and laspartomycin. 31 Structural homology is greater within each group, yet it is also considerable between them (cf.…”

A High‐Resolution Crystal Structure that Reveals Molecular Details of Target Recognition by the Calcium‐Dependent Lipopeptide Antibiotic Laspartomycin C

“…At present, daptomycin is the only clinically used CDA, and its mode of action is the topic of ongoing investigation 6, 7, 8, 9. By comparison, the structurally similar CDAs laspartomycin C, friulimycin B, tsushimycin, and amphomycin have more clearly understood antibacterial mechanisms 10, 11, 12, 13, 14. It was recently reported that laspartomycin C forms a high‐affinity complex ( K d =7.3±3.8 n m ) with the bacterial cell wall precursor undecaprenyl phosphate (C 55 ‐P) and in doing so inhibits peptidoglycan biosynthesis, ultimately leading to cell death 14.…”

Antibiotic discovery in the twenty-first century: current trends and future perspectives

“…19 The scenario is even more disappointing for compounds targeting Gram-negative pathogens, in which old drugs have been revamped for new uses, and none of them has reached phase III yet (Table 1). Ceftazidime is a marketed cephalosporin being developed in combination with NXL104, a representative of a new class of b-lactamase inhibitors, 20 which renders cephalosporin effective against most b-lactamase-producing enterobacteria.…”