| Dangerous, antibiotic resistant bacteria have been observed with increasing regularity over the past several decades. Though bacterial evolution of antibiotic resistance mechanisms is a naturally occurring process, evidence strongly suggests that human mismanagement of antibiotics has greatly accelerated this process. A concurrent decline in research and development by the pharmaceutical industry has led to a deficiency of new antibacterial agents to fight these emerging threats.;The semi-synthetic modification of members of existing antibiotic classes is one approach that has been successfully used to generate new antibacterial agents. Three families of modified aminoglycosides were synthesized. Their affinities for the primary intracellular target of aminoglycosides, the ribosomal A-site, were evaluated using an in vitro Forster resonance energy transfer (FRET)-based assay. Their antibacterial efficacy was quantified by determining minimum inhibitory concentration (MIC) values against resistant bacterial strains.;Singly or doubly modified guanidino-aminoglycosides were synthesized by selectively converting aminoglycoside primary alcohols or primary amines into guanidinium groups. They exhibited superior A-site binding in almost all cases and in some cases greater antibacterial efficacy as compared to their parent aminoglycosides. Particularly promising was an amikacin derivative modified at the 6'' position.;Aminoglycoside amines were globally converted to guanidinium groups to produce guanidinoglycosides. Guanidinoglycosides mostly showed comparable A-site affinities to their parent compounds, but their antibacterial activity was completely compromised.;Tobramycin and amikacin, two of the most clinically used aminoglycosides, were selectively modified with various hydrogen bonding moieties at their 6'' positions. Almost all of these analogs had greater affinities for the A-site. Tobramycin derivatives showed overall disappointing antibacterial activity, but several amikacin analogs showed potent and broad-spectrum antibacterial activity against resistant bacteria.;Aromatic analogs of the lead compound TAN-1057 were synthesized. Some analogs were evaluated in the previously described manner and also in eukaryotic and prokaryotic in vitro translation assays. The analogs showed inconclusive or poor activity in all assays. An alternate synthesis of the surrogate TAN-1057 side chain, beta3-lysine was also devised. An inability to resolve racemic beta3-lysine has thus far stymied the utility of this method, however. |
