Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance

Abstract

Pleuromutilins are antibiotics that selectively inhibit bacterial translation and are semisynthetic derivatives of the naturally occurring tricyclic diterpenoid pleuromutilin, which received its name from the pleuromutilin-producing fungus Pleurotus mutilus Tiamulin and valnemulin are two established derivatives in veterinary medicine for oral and intramuscular administration. As these early pleuromutilin drugs were developed at a time when companies focused on major antibacterial classes, such as the β-lactams, and resistance was not regarded as an issue, interest in antibiotic research including pleuromutilins was limited. Over the last decade or so, there has been a resurgence in interest to develop this class for human use. This has resulted in a topical derivative, retapamulin, and additional derivatives in clinical development. The most advanced compound is lefamulin, which is in late-stage development for the intravenous and oral treatment of community-acquired bacterial pneumonia and acute bacterial skin infections. Overall, pleuromutilins and, in particular, lefamulin are characterized by potent activity against Gram-positive and fastidious Gram-negative pathogens as well as against mycoplasmas and intracellular organisms, such as Chlamydia spp. and Legionella pneumophila Pleuromutilins are unaffected by resistance to other major antibiotic classes, such as macrolides, fluoroquinolones, tetracyclines, β-lactam antibiotics, and others. Furthermore, pleuromutilins display very low spontaneous mutation frequencies and slow, stepwise resistance development at sub-MIC in vitro. The potential for resistance development in clinic is predicted to be slow as confirmed by extremely low resistance rates to this class despite the use of pleuromutilins in veterinary medicine for >30 years. Although rare, resistant strains have been identified in human- and livestock-associated environments and as with any antibiotic class, require close monitoring as well as prudent use in veterinary medicine. This review focuses on the structural characteristics, mode of action, antibacterial activity, and resistance development of this potent and novel antibacterial class for systemic use in humans.

Figure 1.

Structure of pleuromutilin with numbering system (Arigoni 1968). (Left panel from Lindsey 2006.)

Figure 2.

Structures of side chains at C22. Side chains of various pleuromutilin derivatives: (A) veterinary, (B) topical human, and (C) systemical human.

Figure 3.

Lefamulin positioning in the peptidyl transferase center (PTC). PTC of the bacterial ribosome in relation to the positions of A- and P-site tRNA. Red, Lefamulin; blue, A-site tRNA; teal, P-site tRNA.

Figure 4.

Interaction network. (A) The tricyclic pleuromutilin core and sulfanylacetyl as well as acylcarbamate linker (side chains omitted for clarity), and (B) the C14 side chain extension with nucleotides of the peptidyl transferase center (PTC). Hydrogen bonds are shown as dotted lines (Schlunzen et al. 2004; Davidovich et al. 2007; Eyal et al. 2015).