Pleuromutilins: Pleuromutilin (R = HO) (Supplementary Table ) is an antibiotic natural product isolated from Clitopilus scyphoides and Clitopilus passeckerianus (originally Pleurotus mutilis). Four analogs of pleuromutilin are used as antimicrobial agents. Tiamulin and valnemulin are both used as veterinary drugs. Retapamulin (Altabax) was approved by the US FDA in 2007 for treating impetigo caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes. 200 Lefamulin (Xenleta) was approved by the US FDA in 2019 as a treatment for community-acquired bacteria pneumonia. Pleuromutilins are effective against a variety of Gram-positive pathogens, including Streptococcus and Staphylococcus species and Enterococcus faecalis and faecium; they also are effective against Gram-negative bacteria including Haemophilus and Neisseria species, Moraxella catarrhalis, Legionella pneumoniae, Mycobacterium tuberculosis. Mycoplasmas, ureaplasmas, and Chlamydia species are inhibited by pleuromutilins. Lefamulin can potentially cause QT prolongation and thus severe or fatal arrhythmia. Pleuromutilins bind to the 50S subunit of the bacterial ribosome 194 at the PTC, preventing protein synthesis; bacteria can evade resistance to them by methylating the rRNA at A2503 or mutating the L3 ribosomal protein to block the binding of pleuromutilins, resistance can also be due to presence of efflux pumps. In addition, Enterobacteriaceae possesses the AcrAB/TolC efflux pump to export pleuromutilins from the cell and avoid their effects. Finally, the lipophilicity of pleuromutilins can reduce their bioavailabilities; prodrugs, however, can improve the permeability of pleuromutilins into cells and thus their antibacterial activities. Analogs of pleuromutilin have been prepared to expand the antibacterial scope of pleuromutilins, mostly by modification of the acyl moiety on the C14 alcohol. Some recent work has disclosed methods for modification of the pleuromutilin skeleton in addition to the pendant ester.