The molecular biology of moenomycins: towards novel antibiotics based on inhibition of bacterial peptidoglycan glycosyltransferases

Abstract

Moenomycins are phosphoglycolipid antibiotics and the only known natural product inhibitors of peptidoglycan glycosytransferases (PGTs). Techniques that would allow facile diversification of the moenomycin structure would facilitate the development of novel antibiotics, which are urgently needed in the wake of multidrug resistant bacterial infections. The cloning and initial characterization of the moenomycin biosynthetic genes has already redefined the minimal moenomycin pharmacophore and now opens the door for the biocombinatorial generation of bioactive moenomycin fragments. Here, we highlight the importance of research on the genetic mechanisms that regulate moenomycin biosynthesis and that confer moenomycin resistance to bacteria in the development of novel anti-infectives based on PGT inhibition.

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

“…As a result, the molecular mechanisms of moenomycin action are now clearer, and better chemical and biological tools have been developed to generate novel phosphoglycolipids for various purposes. In the past, several reviews have covered the occurrence of moenomycin antibiotics in nature as well as their chemistry and biology 4,8,9,12,21,23-30. Some of these reviews are now outdated, while others do not provide a complete overview of the tripartite complexity of chemical manipulations, biosynthesis and the biological properties of moenomycins.…”

ABC transporter genes from Streptomyces ghanaensis moenomycin biosynthetic gene cluster: roles in antibiotic production and export

“…1). This is derivative of NoB, carrying N-acetylglucosamine instead of chinovosamine as a second carbohydrate ring (counting from terminal carboxamide group of NoB) because genes moeR5moeS5 are absent in moeno38-5 and its derivatives (Ostash et al 2007). Results of these experiments, summarized in Fig.…”

“…1), a structurally unique antibiotic that inhibits peptidoglycan biosynthesis (Ostash et al 2007). Whereas beta-lactams target the transpeptidase domain of penicillin binding proteins (PBPs), MmA inhibits the glycosyltransferase domain of PBPs (Ostash et al 2010). MmA is considered a blueprint for the development of a new class of antibiotics against Gram-positive pathogens, necessitating further exploration of biosynthetic approaches to generation and/or overproduction of MmA analogs (Yuan et al 2008, Ostash et al 2009, Makitrinskyy et al 2010).…”

Elucidation of the genetic mechanisms contributing to moenomycin resistance in actinobacteria

“…Furthermore, structural details of interaction between moenomycins and their target, peptidoglycan glycosyltransferases (PGTs; or transglycosylases), have been illuminated [3]. Despite the progress in understanding chemistry and biology of moenomycins, it is not known how MmA-producing bacteria avoid its toxic action [4,5]. Knowledge of such mechanism(s) would help understand and slow down the spread of MmA resistance among pathogens.…”