Antibiotics streptogramin

Leclercq R, Courvalin P (1991) Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob Agents Chemother 35 1267-1272... 

Another example of macrocyclic RCM with a diene-ene was disclosed in 2000 by Meyers and coworkers in the first total synthesis of griseoviridin (223) [ 107]. Griseoviridin is a highly complex member of the family of streptogramin antibiotics, featuring a 23-membered unsaturated bis-lactam core incorporat-... 

Johnston NJ, Mnkhtar TA, Wright GD. (2002) Streptogramin Antibiotics Mode of action and resistance. Curr Drug Targets 3 335-344. 

A complication attending the deprotection of MOM-protected 1,3-dioIs is formation of methylene acetals, which are very difficult to hydrolyse see Scheme 4.257 below). Ghosh and Liu were able to remove two MOM groups protecting a 1,3-diol in the final step of their synthesis of the streptogramin antibiotic Ma-dumycin II [Scheme 4.245],456 The successful method employed tetrabutylam-monium bromide 2 equiv) and an excess of dichlorodimethylsilane in dichloro-methane at 0 cC for 6 h. 

Figure 8 Inactivation of type B streptogramin antibiotics by Vgb lyase. The type B streptogramins such as pristinamycin la (shown) are cyclic depsipeptides. Vgb lyase catalyzes the cleavage of the C-O depsipeptide bond.

Bonfiglio G, Fumeri PM. Novel streptogramin antibiotics. Expert. Opin. Investig. Dmgs 2001 10 185-198. 

In the laboratory of A.I. Meyers, the first enantioselective total synthesis of the streptogramin antibiotic (-)-madumycin II was achieved. The natural product contains an oxazole moiety, which may be considered a masked dehydropeptide. The oxazole moiety was introduced in two steps by the Burgess cyciodehydration reaction followed by oxidation of the resulting oxazoline to the corresponding oxazole. 

In a broad sense, the term macrolides is used in the same way as the term MLS antibiotics, which include macrolide, lincosamide, and type B streptogramin antibiotics. A single group of macrolide antibiotics is hereafter referred to as macrolide antibiotics. 

It is widely accepted that MLS antibiotics inhibit protein synthesis by binding to closely related sites on the 508 subunit of the 70S ribosome of bacteria [4], despite being structurally different from each other (see Figs. 1 and 2 in a later section). That is the reason why, when inducible resistant Staphylococcus aureus cells are exposed to a low concentration of the drug (0.05 tg erythromycin/ml - 6.8 x 10 M), they show resistance against not only erythromycin but also other macrolide antibiotics as well as lincosamide and type B streptogramin antibiotics. Erythromycin has been widely used and has been the object of extensive molecular and biological studies. 

The molecular biological mode of action of macrolide antibiotics and the biochemical and genetic mechanism of resistance to macrolide, lincosamide, and type B streptogramin antibiotics were reviewed in this chapter. 

The streptogramins are a group of natural occurring antibiotics isolated from Streptomyces pristinasprialis. The streptogramin antibiotics consist of A-type molecules and B-type molecules, which when combined have a synergistic activity. The mechanism of action of the two different types of molecules appear to be quite different. 

Chloramphenicol is a bacteriostatic agent that binds to the 508 ribosomal subunit and inhibits the transpeptidation in protein synthesis. While this agent is not widely used to treat staphylococcal infection, resistance to chloramphenicol is due to inactivation of the antibiotic by chloramphenicol acetyltransferase enzyme (CA7). Macrolides, such as erythromycin and oleandomycin lincosamides, such as lincomycin and clindamycin and streptogramin antibiotics also have a bacteriostatic effect on Staphylococcus spp. by binding to their 508 ribosomal subunit, arresting protein synthesis, but resistance to these antibiotics is also prevalent. Rifampin has also been used to treat staphylococcal infections, but when used alone, resistant strains quickly arise. 

In a later study, Helquist and co-workers adapted this methodology for preparing an advanced optically active intermediate in a synthetic approach to type A streptogramin antibiotics. Treatment of 960 and activated zinc with 957 afforded the alcohol (not shown) that was subjected to a Swern oxidation to produce the desired ,/i-diene 961 (Scheme 1.257). The authors noted that the addition reaction yielded 50% of the intermediate alcohol together with 30—40% recovered 960 regardless of the amount of 957 used. 

Brennan and Campagne" also targeted a protected form of 1229 in their approach to the oxazole-dienyl amine fragment of the group A streptogramin antibiotics (Scheme 1.315). However, these authors installed the oxazole ring as the... 

The first streptogramin antibiotic that has been marketed (in 1999) under the trademark Synercid is a mixture of the S. quinupristin and dalfopristin, which act syneigistically against various methicillin- and vancomycin-resistant Gram-positive bacteria. ... 

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