Fluoroquinolones, a class of type-II topoisomerase inhibitors, have successfully been used as antibiotics for the last several decades, beginning with the use of nalidixic acid in urinary tract infections. This led to the broad-spectrum activity of ciprofloxacin in the 1980s. Unfortunately, use of fluoroquinolones has led to the emergence of resistant bacteria. Recently, this has generated new bacteria such as multidrug-resistant and extensive-drug-resistant strains of M. tuberculosis that are also fluoroquinolone-resistant. Infections caused by these bacterial strains are widespread, with high mortality rate in immune-compromised populations such as the elderly, infants, and in AIDS or HIV-positive patients. Fluoroquinolone resistance is acquired through amino acid substitutions of key fluoroquinolone-binding residues of the type-II bacterial topoisomerases DNA Gyrase and Topoisomerase IV, the enzyme targets of fluoroquinolones. Amino acid substitutions that result in fluoroquinolone resistance are located on Helix-4 of these enzymes, which is the site of a magnesium (Mg)-water bridge that is a crucial binding interaction for fluoroquinolones. When certain substitutions to Helix-4 occur, the Mg-water bridge is compromised and no longer available to anchor fluoroquinolones into a ternary complex composed of topoisomerase, fluoroquinolone, and DNA. This results in drug resistance. Herein are described attempts to generate fluoroquinolones that are capable of overcoming this mechanism of resistance. In the first study, attempts were made to generate a series of novel tricyclic fluoroquinolones and diones designed to exploit intercalative or pi-stacking binding interactions with the bacterial DNA in the ternary complex in order to lessen the importance of the Mg-water bridge interaction. Despite numerous attempts, no complete synthetic pathway to these core structures was ever discovered. The second study investigated the utility of a C7-aminomethylpyrrolidine group on the fluoroquinolone structure. This was done in order to explore the mechanistic reasons why previously generated fluoroquinolones possessing this C7-aminomethylpyrrolidine group maintained activity against common Helix-4 mutants. A panel of fluoroquinolones with C7-aminomethylpyrrolidine groups and diverse core structures was synthesized and docking studies with the original C7-aminomethylpyrrolidine fluoroquinolone and other fluoroquinolones were performed. Target compounds were synthesized and evaluated for inhibition/poisoning purified enzyme and for the ability to inhibit growth with wild-type and fluoroquinolone-resistant cells. In a third study, fluoroquinolones possessing structural variations of the C7-aminomethylpyrrolidine were designed and synthesized to explore structural requirements of the aminomethylpyrrolidine group binding and overcoming fluoroquinolone-resistance caused by alterations of Helix-4. This led to further exploration of the binding space around the C7-position of the fluoroquinolones. In both the second and third studies, the new fluoroquinolones were evaluated for the ability to specifically target bacterial topoisomerases over human topoisomerase. The results of these studies have contributed new knowledge to the binding requirements of fluoroquinolones that maintain potency against fluoroquinolone-resistant type-II topoisomerases, and represent a step towards methodology to overcome bacteria resistant to fluoroquinolones.