Liposidomycin C

Cell wall biosynthesis represents a valid target for antibacterial action but only a limited number of chemical structure classes selectively interact with specific enzymes or protein structures like transporters of the cell envelope. The integral membrane protein MraY translocase is essential for peptidoglycan biosynthesis catalysing the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl phosphate, thereby generating the cell wall intermediate lipid I. Not present in eukaryotic cells, MraY is a member of the superfamily of yet not well-understood integral membrane enzymes which involve proteins for bacterial lipopolysaccharide and teichoic acid or eukaryotic N-linked saccharides biosynthesis. Different natural nucleoside antibiotics as inhibitors of MraY translocase have been discovered comprising a glycosylated heterocyclic pyrimidin base among other potential lipid-, peptidic- or sugar moieties. Caprazamycins are liponucleoside antibiotics isolated from Streptomyces sp. MK730-62F2. They possess activity in vitro against Gram-positive bacteria, in particular against the genus Mycobacterium including M. intracellulare, M. avium and M. tuberculosis. Structural elucidation revealed the (+)-caprazol core skeleton as a unique moiety, the caprazamycins share with other MraY inhibitors such as the liposidomycins, A-90289 and the muraminomicins. They also share structural features such as uridyl-, aminoribosyl- and fatty acyl-moieties with other MraY translocase inhibitors like FR-900493 and the muraymycins. Intensive studies on their biosynthesis during the last decade identified not only common initial biosynthetic steps, but also revealed possible branching points towards individual biosynthesis of the respective compound. Structural diversity of caprazamycins was generated by feeding experiments, genetic engineering of the biosynthetic gene clusters and chemical synthesis for structure activity relationship studies with its target, MraY translocase.

Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.

Liposidomycin is a uridyl liponucleoside antibiotic isolated from Streptomyces griseosporeus RK-1061. It was discovered by Isono in 1985, who had previously isolated and developed a related peptidyl nucleoside antibiotic, polyoxin, a specific inhibitor of chitin synthases, as a pesticide. He subsequently isolated liposidomycin, a specific inhibitor of bacterial peptidoglycan biosynthesis from actinomycetes, using a similar approach to the discovery of polyoxin. Liposidomycin has no cytotoxicity against BALB/3T3 cells but has antimicrobial activity against Mycobacterium spp. through inhibition of MraY (MurX) [phospho-N-acetylmuramoyl-pentapeptide transferase (translocase I, EC 2.7.8.13)]. Since the discovery of liposidomycin, several liposidomycin-type antibiotics, including caprazamycin, A-90289, and muraminomycin, have been reported, and their total synthesis and/or biosynthetic cluster genes have been studied. Most advanced, a semisynthetic compound derived from caprazamycin, CPZEN-45, is being developed as an antituberculosis agent. Translocase I is an interesting and tractable molecular target for new antituberculosis and antibiotic drug discovery against multidrug-resistant bacteria. This review is dedicated to Dr Isono on the occasion of his 88th birthday to recognize his role in the study of nucleoside antibiotics.