Antibiotic resistance is an inescapable problem in the current world of pharmacology. All antibiotics have theoretically limited life spans, as bacteria can pass modes of resistance both vertically to their progeny and horizontally to their neighbors. Organic chemists dealing with the problem of antibiotic resistance are crafting new antibiotics both from existing antibiotic scaffolds and completely de novo. However, in recent years research in new antibiotics has declined rapidly, mainly due to financial considerations - pharmaceutical corporations no longer see the value in spending millions on antibiotic research that may amount to nothing, and that may not end up significantly improving the bottom line even if approved. Current efforts in antibiotic research are mainly focused on making changes to existing antibiotic scaffolds. The majority of approved and Phase III trial antibiotics from the last 10 years are semisynthetic versions of naturally derived antibiotics. This class of antibiotics seems to be the most effective at combating antibiotic resistance. Among this type of antibiotic are the macrolides and ketolides, identified by the presence of a large macrocyclic lactone ring (macrolide ring). All macrolide antibiotics target the 50S subunit of the bacterial ribosome by reversibly binding in the peptidyl transferase center, thus blocking protein synthesis. Telithromycin (TEL), used in clinic since 2004, and cethromycin (CET) are third generation semisynthetic drugs derived from flagship macrolide antibiotic erythromycin. All macrolide antibiotics hitherto have been semisynthetic modifications on the erythromycin scaffold and majority of them are ineffective against multi-drug resistant pathogens. Recently, utilizing structural ribosomal data of RNA mutations, 2009 Nobel laureate Steitz has argued that bacterial resistance to erythromycin and telithromycin may in some cases, be due to a steric clash at the C4-methyl of the antibiotic with a mutant subunit of rRNA. Based on this, Andrade and co-workers have hypothesized that replacing the said methyl with hydrogen would lessen the steric interference and defeat the antibiotic resistance. To this end, the Andrade Lab launched a structure-based drug design program that encompassed the preparation and biological evaluation of four desmethyl (i.e., CH3 -- H) analogues of TEL: 4,8,10-tridesmethyl TEL, 4,10-didesmethyl TEL, 4,8-didesmethyl TEL, 4-desmethyl TEL. As a part of my dissertation I accomplished the total syntheses and biological evaluation 4,8-didesmethyl TEL (36 steps) and 4,8,10-tridesmethyl CET (41 steps). The CET analog was an extension to the tridesmethyl scaffold, initiated based upon optimistic results with the corresponding TEL analog. Apart from these two molecules, I have also reported my contributions toward the total synthesis of 4,8,10-tridesmethyl and 4-desmethyl TEL. / Chemistry