Antibacterial Antifolates: From Development through Resistance to the Next Generation

The folate cycle is one of the key metabolic pathways used by bacteria to synthesize vital building blocks required for proliferation. Therapeutic agents targeting enzymes in this cycle, such as trimethoprim and sulfamethoxazole, are among some of the most important and continually used antibacterials to treat both Gram-positive and Gram-negative pathogens. As with all antibacterial agents, the emergence of resistance threatens the continued clinical use of these life-saving drugs. In this article, we describe and analyze resistance mechanisms that have been clinically observed and review newer generations of preclinical compounds designed to overcome the molecular basis of the resistance.