Pleuromutilin

Pleuromutilin and its derivatives are antibacterial drugs that inhibit protein synthesis in bacteria by binding to the peptidyl transferase component of the 50S subunit of ribosomes.

[10] Its synthetic bottleneck lays on the production of the precursor GGPP and the following formation of the tricyclic structure, which is catalyzed by Pl-cyc, a bifunctional diterpene synthase (DTS).

Subsequently, variable 1,2-proton and methyl shifts occur to translocate the carbocation towards one of the two interconnecting C-atoms and this intermediate induces a base-catalyzed ring contraction.

On the other hand, at the C-terminal end it has a class I DTS domain, which catalyzes a conjugated dephosphorylation, generating the 8-membered cyclic core, followed by a 1,5-proton shift and a stereospecific hydroxylation to obtain premutilin.

The short-chain dehydrogenase/reductase enzyme (Pl-sdr) has a regiospecific activity and converts the 3-hydroxy group to a ketone, forming the intermediate mutilin.

Proposed biosynthetic pathway of pleuromutilin. [ 12 ] [ 13 ] The left part of the scheme represents a general biosynthetic approach for Geranylgeranyl pyrophosphate (GGPP). The following cyclisation steps to the pleuromutilin tricyclic core will be provided by class II and class I terpene synthase domain of Pl-cyc . Final catalytic, stereospecific hydroxylation at C-11 and C-3 ( Pl-p450-1, Pl-p450-2 ), regiospecific oxidation of the 3-hydroxy group to a ketone ( Pl-sdr) , acetyl-group-transfer at OH-14 ( Pl-atf) and final hydroxylation at the α-acetyl position ( Pl-p450-3 ) will lead to pleuromutilin. [ 11 ]