Moenomycins

Scheme 4.63 Multiple use of the sulfoxide glycosylation in the synthesis of the moenomycin A pentasaccharide.

Other aminoglycosides include rnnilamycin, moenomycin, and fosfomycin. 

Materials differ significantly with the kind of target and selection procedure. Here we list materials used for the example selection of moenomycin A-specific 2 -modified RNA aptamers (Section 7.3.6). 

Moenomycin-S-S-pyridone (gift from Peter Welzel, Leipzig)... 

For chromatographic selection, moenomycin A-derivatized matrix was produced by incubating prepared thiol sepharose (described in [28]) with moenomycin-S-S-pyridone for 3h at 4°C by gently swirling in immobilization buffer (Figure 7.4). 

The released 2-thiopyridone was quantified by UV spectroscopy (343 rnn) to determine the amount of immobilized moenomycin A. 

The moenomycin-sepharose was stored in selection buffer at 4 °C and could be used for about 2 weeks. 

Thiol Sepharose 4B derivatized with moenomycin A was incubated with the preselected RNA pool for 1 h at room temperature while being mixed gently. This mixture was then transferred to an empty chromatography column. Unbound RNA was removed from the matrix by washing with selection buffer. Bound RNA was eluted by cleaving the moenomycin A from the Sepharose by washing the column 5 times with 200 pL selection buffer containing 200 mM DTT. 

S. Riedel, A. Donnerstag, L. Hennig, P. W. Richter, K. Hobert, and D. M. van Heijenoort, Synthesis and transglycosylase-inhibiting properties of a disaccharide analogue of moenomycin A lacking substitution at C-4 of unit F, Tetrahedron, 55 (1999) 1921-1936. 

This family is exemplified by moenomycin A 77, a major representative of moeno-mycin complex produced by S. ghanaensis (ATCC14672). Compound 77 is one of the most potent antibiotics known to date it is active against many vancomycin-and methicillin-resistant pathogens [141]. Moenomycin A suffers from poor pharmacokinetics, prompting the search for improved analogs that are suitable for treating human diseases. 

Several derivatives of 77 were recently generated using GT gene disruption and heterologous expression techniques [142-144]. Of notable interest is the compound neryl-moenomycin A (n-MmA) 78, which is simpler than the long-thought minimal pharmacophore and yet displays antibiotic activity [143, 144]. 

Ostash B, Saghatelian A, Walker S (2007) A streamlined metabolic pathway for the biosynthesis of moenomycin A. Chem Biol 14 257-267... 

Yuan Y, Fuse S, Ostash B et al (2008) Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implication for antibiotic design. ACS Chem Biol 3 429 136... 

Ostash B, Doud E, Lin C et al (2009) Complete characterization of the seventeen step moenomycin biosynthetic pathway. Biochemistry 48 8830-8841... 

Some members of class A high-molecular-mass PBPs were found to bind to moenomycin [64,94], E. coli PBP la and lb were purified by using moenomycin-affinity column chromatography in combination with other column chromatographic methods. 

F Huber, F Nesemann. Moenomycin an inhibitor of cell wall synthesis. Biochem Biophys Res Commun 30 7-13, 1968. 

Scheme 5.1.5. Clostripain-mediated coupling of the Leu-enkephalin sequence Z-Asp-Tyr-Gly-Gly-Phe-Leu-OH with a moenomycin A analog.

The level of LPG also influences the susceptibility of an MRSA strain to other antibiotics. A transposition mutant defective in mprF was less susceptible to moenomycin, but more susceptible to oxacillin, methicillin and gentamicin.41 Recent studies have shown that DapR strains have increased ratios of LPG/ PG,42 or increased amounts of LPG in the outer leaflet of the membrane, thus increasing the surface positive charge.43 This indicates that the mutations have enhanced ability to couple lysine to PG or to flip LPG to the outer leaflet. Deletion of mprF increases susceptibility to daptomycin by about four-fold in S. aureus.43,44 Disruption of mprF in B. subtilis caused a two-fold reduction in daptomycin MIC.34... 

Figure 4.8 Structure of a moenomycin-inspired SP discrete library L7.

Sofia et al. (41) reported a SP library of disaccharides L7 made by 1300 individuals and inspired by the disaccharide core of moenomycin A, a bacterial cell wall inhibitor (Fig. 4.8). Both the structure of the library and its main features are shown in Fig. 4.8. The four major disaccharide scaffolds (X, Y, and W variations) were either built on resin via glycosylation or attached onto the photolabile linker, and subsequently decorated by introduction of Ri, R2, and R3 radiofrequency encoding (42) was used to obtain a large number of discretes with an affordable number of reactions. The... 

SYNS BAMBERMYCIN FIjWOMYCIN FLAVO-PHOSPHOLIPOL MENOMYCIN MOENOMYCIN A... 

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