Moenomycin family antibiotics: chemical synthesis, biosynthesis, and biological activity

Abstract

The review (with 214 references cited) is devoted to moenomycins, the only known group of antibiotics that directly inhibit bacterial peptidoglycan glycosytransferases. Naturally occurring moenomycins and chemical and biological approaches to their derivatives are described. The biological properties of moenomycins and plausible mechanisms of bacterial resistance to them are also covered here, portraying a complete picture of the chemistry and biology of these fascinating natural products

Pseudomonas Aeruginosa : Targeting Cell-Wall Metabolism for New Antibacterial Discovery and Development

“…Moreover, moenomycin-family antibiotics are generally ineffective against Gram-negatives due to their inability to cross the OM [123]. Recognizing this problem, recent studies have increased efforts to discover LMW compounds with TG-inhibitory activity [86,121] (Table 2).…”

Structural Insights into Inhibition of Escherichia coli Penicillin-binding Protein 1B

“…Taken together, the EF ring phosphonate portion of moenomycin makes an intricate network of hydrogen bonding interactions with conserved residues in and around the E. coli PBP1b catalytic site that are essential for polymerization of the natural substrate. This observation underpins the fact that despite the widespread use of moenomycin as a growth promoter in animal feed, no significant resistance mechanisms have been detected (8). The ability of moenomycin to mimic key interactions of the donor substrate combined with its unprecedented tight binding affinity provides a substantial genetic barrier to the development of resistance by target modification.…”

“…The Streptomyces phosphoglycolipid natural product moenomycin is the best characterized PG GTase inhibitor and displays inhibitory constants in the nanomolar range (8). Moenomycin is widely used as a growth promoter in animal feed yet is not effective in humans largely because of poor absorption resulting in suboptimal pharmacokinetic properties (9).…”

Positive cooperativity between acceptor and donor sites of the peptidoglycan glycosyltransferase

“…Two main strategies are being followed to identify novel pharmacophore lead molecules for the design and synthesis of new GT inhibitors that could be developed as antibiotics: high throughput screening of chemical libraries [2][3][4] and rational synthesis of substrate and moenomycin (GT inhibitor) analogs [5][6][7][8]. The second strategy requires a deep understanding of the GT mechanism and structural data on protein-ligand complexes.…”