The Janus Effect: The Biochemical Logic of Antibiotic Resistance.

Abstract

Antibiotics are essential medicines threatened by the emergence of resistance in all relevant bacterial pathogens. The engagement of the molecular targets of antibiotics offers multiple opportunities for resistance to emerge. Successful target engagement often requires passage of the antibiotic from outside into the cell interior through one or two distinct membrane barriers. Resistance can occur by preventing the accumulation of antibiotics in sufficient quantities outside the cell, decreasing the rates of entry into the cell, and modifying the antibiotic or the target once inside the cell. These competing equilibria and rates are the lens through which the balance of antibiotic efficacy or failure can be viewed. The two faces of antibiotics, cell growth inhibition or resistance, are reminiscent of Janus, the Roman god of doorways and beginnings and endings, and offer a framework through which antibiotic discovery, use, and the emergence of resistance can be rationally viewed.