Development of Microbe-Selective Antibacterial Agents: From Small Molecules to Siderophores

Anitibiotic resistance is developing at an alarming rate and is one of the world's most pressing health problems. New methods for developing microbe-selective antibacterial agents including novel small molecules and molecular antibiotic delivery systems that challenge existing bacterial resistance mechanisms and limit the emergence of resistance are described in this dissertation. Siderophores are multidentate Fe(III) chelators used by bacteria for Fe-assimilation. Siderophores are important therapeutic agents in the treatment of chronic Fe-overload diseases. Sideromycins, also called siderophore-antibiotic conjugates, are a unique subset of siderophores that enter bacterial cells via siderophore uptake pathways and deliver a toxic antibiotic in a 'Trojan Horse' fashion. Sideromycins represent a novel antibiotic delivery technology with untapped potential for developing sophisticated microbe-selective antibacterial agents. Significant advancements in the design, syntheses, and understanding of sideromycins are described in Chapters 2-6. Linear trihydroxamate sideropohores were found to be Gram-positive selective antibiotic delivery vectors and the full trihydroxamate siderophore backbone was necessary for siderophore-associated active transport into bacterial cells. Maintaining high Fe(III)-affinity was important for sideromycins to compete with siderophores for entry into bacterial cells. Changing the siderophore structure changed the microbe-selectivity of sideromycins. Antibiotics with intracellular targets were useful against Gram-positive pathogens and antibiotics with periplasmic targets were useful against Gram-negative pathogens. Sideromycins were found to bring new life to antibiotics that fail to enter bacterial cells due to permeability problems. Finally, a microbe-triggered antibiotic release process was not required for activity, but was desired to maximize sideromycin potency. The work from Chapters 2-6 culminated with the discovery of a trihydroxamate-fluoroquinolone sideromycin with potent and selective activity against Staphylococcus aureus SG511 (MIC90=1 ÌÂM) and a mixed ligand biscatecholate-monohydroxamate-Ì¢-lactam sideromycin with potent and selective activity against Acinetobacter baumanii ATCC 17961 (MIC90=0.0078 nM). The discovery of a structurally novel small molecule antibacterial scaffold based on N-alkyl-N-(pyridin-2-yl)hydroxylamines is described in Chapter 7. The scaffold was discovered from antibacterial testing of a compound library generated from nitroso Diels-Alder and ene chemistry. The scaffold had selective and potent antibacterial activity against Micrococcus luteus ATCC 10240 (MIC90=2 ÌÂM) and other Gram-positive organisms, including resistant strains of S. aureus (MRSA) and E. faecalis (VRE).