Mupirocin

Mupirocin binds reversibly to the catalytic center of bacterial isoleucyl-tRNA synthetase (IRS) and thus causes a block in protein biosynthesis. Eukaryotic IRSs as well as the homolog of the mupirocin-producing P. fluorescens exhibit lower affinity for the antibiotic. Since the early 1990s, however, highly resistant bacterial strains are known that carry plasmids with a second IRS gene. This IRS variant is less efficiently inhibited by mupirocin and seems to be derived from a eukaryotic ancestor.

In conclusion, a convergent total synthesis of mupirocin H has been achieved. Initial studies revealed an interesting rearrangement of a δ-lactone to a γ-lactone during protection of syn diols 17, 18 and 20 providing a valuable entry to such compounds. The key features of the total synthesis included a stereoselective alkylation of trisubstituted d-lactone 22 with iodide 5 under conditions which avoid competing b-elimination thus generating the carbon framework of mupirocin H with all six stereogenic centres in place. Reductive cleavage of the lactone 23 via trapping an intermediate lactol as the dithiolane followed by a Raney® nickel reduction delivered the required 6-methyl group. Finally selective functional group manipulations yielded the target. This approach should be readily adapted for the synthesis of metabolites such as mupirocin W lacking the central THP core which arise during pseudomonic biosynthesis giving a further insight into trans-AT PKS biosynthetic pathways of much current interest. These studies are ongoing in our laboratory.

Mupirocin: mupirocin is an extensively investigated polyketide antibiotic produced by the soil dwelling Gram negative bacterium Pseudomonas fluorescens NCIMB 10586. Since its initial discovery in 1970s, mupirocin and several of its analogs have been isolated from other Pseudomonas strains, as well as marine bacteria. Mupirocin has a broad spectrum of activity19 and is commercially available as Bactroban or Centany which is a polyethylene glycol suspension of 2% mupirocin. These compounds are extensively used for the treatment of skin infections, including those caused by methicillin resistant Staphylococcus aureus (MRSA), and have been shown to inhibit the formation of biofilms by S. aureus under conditions where vancomycin and ciprofloxacin are ineffective.