There are some liabilities to Daraprim (pyrimethamine), however. Trimethoprim is a substrate for bacterial P/gp drug transporters. 166 Klebsiella pneumoniae and Serratia marscens show resistance to Daraprim (pyrimethamine) because they alter their cell membranes to inhibit passive transport, preventing drugs from exerting their effects. In addition, sulfa drugs may have severe hypersensitivity reactions. To avoid sulfonamide-induced hypersensitivity reactions, researchers have sought trimethoprim analogs that can be used as monotherapies. One such compound is iclaprim, which has been tested as a monotherapy against acute bacterial skin and skin structure infections and communityacquired pneumonia. Two different companies, Arpida AG and Motif BioSciences, have attempted to gain approval for iclaprim. Arpida's application to the US FDA was rejected because it was not sufficiently non-inferior to the standard of care. Motif performed multiple Phase 3 studies on iclaprim ; however, its approval would have required additional studies to address potential liver toxicity. Quinolones: Quinolones are a family of synthetic broad-spectrum antibiotics whose basic structure is an N-1 alkylated 3-carboxypyrid-4-one ring fused to another aromatic ring, i.e. a bicyclic core structure related to a 4-quinolone. Usually included with the quinolone family is the 1,8-naphthyridone core (X=N). The first publication of quinolone structures having antibacterial activity was a patent by Imperial Chemical Industries (ICI) published in 1960 176 , this was followed by Sterling disclosing the antibacterial properties of 1,8-naphthyridones 177 and nalidixic acid. Modifications to the base structure can enhance activity, control potency, and influence pharmacokinetics, though positions 3 and 4 are crucial for enzyme binding and should not be altered. Most common modifications are substitutions on carbon 5,6,7, and 8. The addition of fluoro to the C-6 position is the key characteristic of a large subset of quinolones called fluoroquinolones. This includes ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, sparfloxacin, delafloxacin, trovafloxacin, and many others. This family of antibiotics, depending on the member, can target gram-positive and gram-negative bacteria by inhibiting bacterial topoisomerase II, DNA gyrase, and DNA topoisomerase IV enzymes; this mechanism of action interferes with DNA synthesis and preventing the replication process. Still, growing bacterial resistance is raising concerns in the use of this class of antibiotics. Three main mechanisms of resistance have been documented: target-mediated resistance, plasmid-mediated resistance, and chromosome-mediated resistance. More information on these mechanisms can be found in recent reviews by Maxwell et al. , Tang and Zhao 181 , and Ruiz. Apart from increasing antimicrobial resistance, debilitating side effects of quinolones and fluoroquinolones are a concern that is restricting their use. on the topic of quinolones, thoroughly discuss synthetic advances, 187 emerging antibiotics, 188 and the application of metal complexes in the context of quinolones. 189