Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae

Abstract

The continuing increase in antibiotic-resistant microorganisms is driving the search for new antibiotic targets and improved antimicrobial agents. Ketolides are semisynthetic derivatives of macrolide antibiotics, which are effective against certain resistant organisms. Solithromycin (CEM-101) is a novel fluoroketolide with improved antimicrobial effectiveness. This compound binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis. Like other ketolides, it should impair bacterial ribosomal subunit formation. This mechanism of action was examined in strains of Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. The mean 50% inhibitory concentrations (IC 50 s) for solithromycin inhibition of cell viability, protein synthesis, and growth rate were 7.5, 40, and 125 ng/ml for Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The net formation of the 50S subunit was reduced in all three organisms, with IC 50 s similar to those given above. The rates of 50S subunit formation measured by a pulse-chase labeling procedure were reduced by 75% in cells growing at the IC 50 of solithromycin. Turnover of 23S rRNA was stimulated by solithromycin as well. Solithromycin was found to be a particularly effective antimicrobial agent, with IC 50 s comparable to those of telithromycin and significantly better than those of azithromycin and clarithromycin in these three microorganisms.

Investigational Antimicrobial Agents of 2013

“…Solithromycin (CEM-101; Cempra) (Fig. 3, compound 5) is a novel fluoroketolide that binds to the 50S ribosomal subunit with an affinity similar to that of telithromycin (83). The antimicrobial activity of solithromycin is directed against respiratory pathogens, with 99.9% of its MICs being Յ0.5 g/ml against the streptococci and with MIC 90 values of 2 g/ml and 0.12 g/ml against Haemophilus influenzae and Moraxella catarrhalis, respectively (84).…”

Efficacy of Solithromycin (CEM-101) for Experimental Otitis Media Caused by Nontypeable Haemophilus influenzae and Streptococcus pneumoniae

“…It binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis, presumably preventing ribosomal subunit formation (16). Rodgers and colleagues reported that solithromy- cin inhibits ribosomal biosynthesis of S. pneumoniae and NTHi at nanogram concentrations, albeit S. pneumoniae was nearly 20-fold more sensitive to its action than to that of NTHi.…”

Maternal Administration of Solithromycin, a New, Potent, Broad-Spectrum Fluoroketolide Antibiotic, Achieves Fetal and Intra-Amniotic Antimicrobial Protection in a Pregnant Sheep Model

“…Not only is it extremely effective against Mollicutes (Ureaplasma and Mycoplasma spp. ), the organisms most commonly isolated from amniotic fluid following preterm labor or PPROM, but it is also highly effective against other important genital tract pathogens, such as group B streptococci, N. gonorrhoeae, and C. trachomatis (32,(34)(35)(36)(37)(38)(39)(40). Assuming that the present findings can be replicated in human pregnancy, then administration of solithromycin to women in preterm labor or PPROM would be expected to constitute a markedly more effective antenatal antimicrobial therapy than currently used macrolides, with commensurate benefits in the reduction of neonatal infections and associated morbidity and mortality.…”

“…Solithromycin (CEM-101) is a novel macrolide/fluoroketolide antibiotic which exhibits broad-spectrum activity against Grampositive and some Gram-negative organisms, including Neisseria gonorrhoeae, Chlamydia trachomatis, Haemophilus spp., streptococci, and enterococci (31)(32)(33)(34)(35)(36)(37). It is exceptionally potent against Ureaplasma parvum, Ureaplasma urealyticum, and Mycoplasma hominis (125 to 250 times more potent than azithromycin) (31).…”