The search for antimicrobial agents effective against bacteria resistant to multiple antibiotics

The discovery, development, and clinical use of antibiotics during the 20th century have decreased substantially the morbidity and mortality from bacterial infections. The antibiotic era began with the therapeutic application of sulfonamide drugs in the 1930s, followed by a “golden” period of discovery from approximately 1945 to 1970, when a number of structurally diverse, highly effective agents were discovered and developed (16). However, since the 1980s the introduction of new agents for clinical use has declined, reflecting both the challenge of identifying new drug classes and a declining commitment to antibacterial drug discovery by the pharmaceutical industry (11, 42, 53, 63). The same period with a reduced rate of introduction of new agents has been accompanied by an alarming increase in bacterial resistance to existing agents, resulting in the emergence of a serious threat to global public health (7, 9, 28, 39, 49, 60, 63, 64). The resistance problem demands that a renewed effort be made to seek antibacterial agents effective against pathogenic bacteria resistant to current antibiotics. This minireview reviews the status of research in this critical therapeutic area. We reevaluate the potential of older, unexploited agents and review current approaches to the discovery of new agents, including the identification of new molecular targets for antibiotic action. Although other approaches such as the use of vaccines, monoclonal antibodies, hematopoiesis-stimulating factors, and various immunoregulatory cytokines may prove to have utility against infections caused by antibiotic-resistant bacteria (7), this minireview is limited to discussion of antibacterial agents and strategies for the detection of new molecular targets.