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Lefamulin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Lefamulin is the first systemically administered pleuromutilin and is available in intravenous and oral formulations. It inhibits bacterial protein synthesis via a specific interaction with the 23S rRNA of the 50S ribosomal subunit. Lefamulin selectively binds to the peptidyl transferase center of the ribosome, to prevent the correct positioning of the CCA ends of tRNAs for peptide transfer (Long et al., 2006). Lefamulin has activity against principally Gram-positive bacteria; it is also active against H. influenzae, M. catarrhalis, Legionella pneumophila, Chlamydophila pneumoniae, and Mycoplasma pneumoniae (Sader et al., 2012a, 2012b). It is currently undergoing clinical trials, conducted by Nabriva Therapeutics. A phase II clinical trial of lefamulin for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) has been completed. A phase III trial of lefamulin for the treatment of community-acquired pneumonia is currently recruiting (clinicaltrials.gov/ct2/show/NCT02813694).
Design, synthesis, biological evaluation and molecular docking studies of novel pleuromutilin derivatives containing nitrogen heterocycle and alkylamine groups
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Qi Wang, Jie Liu, Zi-Dan Zhou, Ke-Xin Zhou, Fei Li, Qi-Wen Zhang, Shou-Kai Wang, Wei Wang, Zhen Jin, You-Zhi Tang
Pleuromutilin (1, Figure 1) is a tricyclic diterpene natural product, which was first discovered and isolated from two basidiomycetes, Pleurotus mutilus and P. passeckerianus in 19517. Pleuromutilin exhibited antibacterial activity towards part of Gram-negative bacteria and most of Gram-positive bacteria, such as Staphylococcus aureus8. Pleuromutilin exerts antibacterial activity by binding to the V domain of the peptidyl transferase centre (PTC) of the 50S subunit of the bacterial ribosome9. Thus, pleuromutilin has aroused considerable research for this unique antibacterial mechanism. The structural optimizations of pleuromutilin on the C-14 side chain prompted the discovery of tiamulin (2, Figure 1) and valnemulin (3, Figure 1) which were authorised as veterinary medicines in 1979 and 1999, respectively10. Retapamulin (4, Figure 1) became the first pleuromutilin approved for human use by U.S Food and Drug Administration (FDA) in 200711. Lefamulin (5, Figure 1) is the first approved systemic pleuromutilin antibiotic for the treatment of community-acquired bacterial pneumonia (CABP)12.
A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zhe Zhang, Zhao-Sheng Zhang, Xiao Wang, Gao-Lei Xi, Zhen Jin, You-Zhi Tang
The naturally tricyclic diterpene product, (+)-pleuromutilin (1, Figure 1), was first isolated from the higher fungi Basidiomycetes Pleurotus species Pleurotus mutiliz and Pleurotus Passeckeranius in 19515. The pleuromutilin class displays potent antibacterial activity especially against gram-positive bacteria and mycoplasmas6. Further studies have identified that pleuromutilin and its analogues could selectively inhibit bacterial protein synthesis through interaction with the peptidyl transferase centre (PTC) of the bacterial 50S ribosomal subunit 23S rRNA7–11. This distinct mechanism of action of pleuromutilin makes it possesses rarely cross-resistance with other classes of clinically used antibacterial drugs, which has inspired researchers to modify its structure to obtain new antibiotics12. The structural optimizations of its C-14 side chain prompted the discovery of tiamulin (2, Figure 1) and valnemulin (3, Figure 1), which were successively approved by the Food and Drug Administration (FDA)13. During the past ten years, retapamulin (4, Figure 1) was approved as a topical antibiotic for human use to treat skin infections in 200914, while lefamulin (5, Figure 1) was approved by the FDA as the first intravenous and oral pleuromutilin antibiotic in 201915,16.
The safety of antimicrobials for the treatment of community-acquired pneumonia
Published in Expert Opinion on Drug Safety, 2020
Carla Bastida, Dolors Soy, Antoni Torres
Lefamulin is the first antimicrobial of the pleuromutilin class to be approved for systemic use in humans. It has a novel mechanism of action, acting by inhibiting bacterial protein synthesis at the A- and P-sites of the peptidyl transferase center of the 50S ribosomal subunit [61]. Recently, it was approved by the FDA for the intravenous and oral treatment of adults with bacterial CAP caused by susceptible microorganisms. Lefamulin has bacteriostatic activity against Gram-positive and atypical organisms associated with CAP (e.g. Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae), with an expanded Gram-positive spectrum that includes methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. The agent has also been shown to retain its activity against multidrug-resistant pathogens that cause sexually transmitted infections (e.g. Neisseria gonorrhoeae and Mycoplasma genitalium) [61,62].