Binding and Action of CEM-101, a New Fluoroketolide Antibiotic That Inhibits Protein Synthesis

Targeting Antibiotic Resistance

“…Therefore, questions remained as to the actual binding mode of solithromycin and telithromycin in pathogenic bacteria. In 2010, Cate, Mankin, and co‐workers crystallized solithromycin as well as telithromycin in complex with the E. coli ribosome and were able to indicate that the placement of these ketolides most likely reflects the binding in S. aureus ribosomes given the sequence conservation of the A752:U2609 base pair among many eubacteria 71, 72…”

“…Indeed, in comparison to non‐fluorinated analogues, the fluorinated versions showed stronger inhibition of the growth of streptococci carrying the erm gene. Interestingly, for solithromycin, weak binding to ribosomes dimethylated at A2058Ec could be detected by chemical probing 71. Key structural features of the ketolides are summarized in Figure 13 (for an example of a ketolide with a 6‐ O ‐attached side chain, see cethromycin) 74, 75…”

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

“…This modification is mediated by methylases encoded in the so-called erm genes (Roberts et al, 1999), resulting in the inability of macrolides to interact with ribosome. Although double methylation reportedly results in general higher levels of macrolide resistance and single methylation results in low levels of macrolide resistance (Vester & Long, 2009), recent reports have shown that the most modern fluoroketolides, such as solithromycin, are able to develop a weak interaction with ribosomes dimethylated at position A2058 (Llano-Sotelo et al, 2010). Although these studies were developed with S. aureus ribosomes, they can probably be extrapolated to Gramnegative microorganisms such as Enterobacteriaceae since solithromycin possesses a high affinity towards E. coli ribosomes (Llano-Sotelo et al, 2010).…”

“…the number of carbon atoms in the macrolactonic ring (Table 1 and Figure 2). Regarding structural modifications, four different classes have been described: those classically referred to as macrolides, such as erythromycin, which were the molecules first described; azalides, like azithromycin, that incorporate a nitrogen in the macrolactonic ring resulting in higher basicity and increasing both acid stability and bioavailability (Mutak, 2007); and ketolides, which possess a keto group at the C3 position of the lactone ring instead of the cladinose sugar found in erythromycin, enhancing their activity spectrum and improving their acid stability, and of which telithromycin is a representative class member (Ackermann & Rodloff, 2003;Schl€ unzen et al, 2003;Zhanel et al, 2002); finally, ketolides such as solithromycin, which incorporate a fluor atom in C2 (fluoroketolides), are currently under development (Llano-Sotelo et al, 2010;Putnam et al, 2010). Additionally, subclasses such as triamilides, which are represented by tulatrhomycin, a tribasic derivative azalide, have also been proposed (Letavic et al, 2002).…”

Renaissance of antibiotics against difficult infections: Focus on oritavancin and new ketolides and quinolones

“…Among more recent generations, one can find molecules like gemifloxacin (marketed in the US and in Korea), which also include Gram-positive anaerobes in their spectrum, or garenoxacin (marketed in Japan), which lacks the fluorine in position 6, giving rise to the desfluoroquinolones subclass (77). Despite the tremendous number of molecules produced, only a few of them were brought on the market, among which some were withdrawn or have seen their use restricted because in telithromycin, may possibly account for the higher intrinsic activity of solithromycin as compared to telithromycin (57). As for other macrolides and ketolides, solithromycin's pharmacokinetic profile is characterized by a broad tissue distribution and high cellular accumulation (58,59), reaching elevated concentrations in alveolar macrophages (24-h AUC: 1500 mg.h/L; ratio to serum concentration: 180) and epithelial lining fluid (24-h AUC: 80 mg.h/L; ratio to serum concentration: 10).…”