At least six macrolides have been approved by the US FDA for treating bacterial infections. Erythromycin (discovered in 1952) is still used to treat a variety of infections, including skin infections, syphilis, and acne. Dirithromycin was approved in 1995 142 for bacterial infections related to chronic bronchitis and for uncomplicated skin or skin-structure infections by nonresistant Staphylococcus aureus, but was withdrawn in 2004. Clarithromycin was approved in 2001: for acute bacterial exacerbation of chronic bronchitis in adults, acute maxillary sinusitis, community-acquired pneumonia, pharyngitis/tonsillitis, uncomplicated skin and skins structure infections, acute otitis media in pediatric patients, treatment and prophylaxis of disseminated mycobacterial infections, and Helicobacter pylori infection and duodenal ulcer disease in adults with methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. Azithromycin was approved in 2002 for treating acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis in adults, uncomplicated skin and skin structure infections, urethritis and cervicitis in adults, genital ulcer disease in men, acute otitis media in pediatric patients, community-acquired pneumonia in adults and pediatric patients, pharyngitis/tonsillitis in adults and pediatric patients from Gram-positive and Gram-negative bacteria. Fidaxomicin was approved in 2011 for treating Clostridium difficile-associated diarrhea. Telithromycin is a ketolide (a macrolide in which a ketone replaces an aminocarbohydrate-substituted alcohol moiety). It was approved by the US FDA in 2004 but withdrawn from sale in 2016 due to severe side effects (liver damage, respiratory failure in myasthenia gravis patients) and resulting restrictions on the approved indications for use. Macrolides bind (as with many other antibiotics) to the 50S subunit of the bacterial ribosome, but not to the PTC, instead blocking the exit tunnel, preventing peptides from leaving the ribosome. Macrolides, however, tend to have larger molecular weights than other antibiotic classes (730-860 Da as opposed to 300-630 Da for others) and to be less polar 150 , which makes them less generally bioavailable to cells and thus less effective. Mutations in the 23S rRNA sequence, acquisition of a methyltransferase to modify the rRNA, generation of a peptide to displace macrolides from the ribosome, phosphorylation or lactone hydrolysis, and efflux pumps can confer resistance to macrolides. Macrolides are generated either directly from Streptomyces species or by semisynthesis from erythromycin or other macrolide isolates. The Myers group (among others) developed modular syntheses of macrolides, allowing variation in substituents, ring size, and polarity that are not possible for semisynthetic macrolides; the complexity of macrolides, their polarity, metabolic stability (to lactone cleavage), and effective charge can be readily varied, yielding amine-substituted macrocycles with improved activity against drug-resistant bacteria and to broaden antibacterial scope. Macrolide Pharmaceuticals was established in 2015 to use the Myers group's methodology to develop novel antibiotics. 153