Phenotypic Tolerance: The Search for β-Lactam Antibiotics That Kill Nongrowing Bacteria

Abstract

beta-Lactam antibiotics rapidly kill bacteria during logarithmic growth but fail to kill nongrowing cells. This trait is the most universal example of phenotypic tolerance (the ability of bacteria to evade the bactericidal activity of antibiotics). Both nongrowing and slowly growing bacteria are found very frequently during infection in vivo, and phenotypic tolerance to the bactericidal activity of antibiotics as a consequence of reduced growth rate can be detected in vivo. With the use of an in vitro model system of nongrowing bacteria, a select group of beta-lactam antibiotics has been found that demonstrates a striking and unusual ability to kill nongrowing bacteria despite phenotypic tolerance to conventional beta-lactam antibiotics. These same compounds also effectively kill phenotypically tolerant cells in cerebrospinal fluid and serum. The extension of bactericidal activity to nongrowing and slowly growing bacteria may be a major advance in efforts to improve the chemotherapy for infectious diseases.