Microbial persistence and the road to drug resistance

Abstract

Microbial drug persistence is a widespread phenomenon in which a subpopulation of microorganisms is able to survive antimicrobial treatment without acquiring resistance-conferring genetic changes. Microbial persisters can cause recurrent or intractable infections, and, like resistant mutants, they carry an increasing clinical burden. In contrast to heritable drug resistance, however, the biology of persistence is only beginning to be unraveled. Persisters have traditionally been thought of as metabolically dormant, nondividing cells. As discussed in this review, increasing evidence suggests that persistence is in fact an actively maintained state, triggered and enabled by a network of intracellular stress responses that can accelerate processes of adaptive evolution. Beyond shedding light on the basis of persistence, these findings raise the possibility that persisters behave as an evolutionary reservoir from which resistant organisms can emerge. As persistence and its consequences come into clearer focus, so too does the need for clinically useful persister-eradication strategies.

Figure 1. Drug persistence and recurrent infection.<

br>Schematic model of killing and persistence kinetics during antimicrobial therapy. Treatment of an initial population of pathogens (I) causes killing of the majority of cells (II), but fails to eradicate a small subset of persisters (III). When antibiotic pressure is removed, persisters resume growth, resulting in recurrent infection of the host (IV). Re-treatment results in similar killing kinetics.

Figure 2. Stress responses link persistence, adaptive evolution and resistance.<

br>In this model, microbial responses to endogenous or exogenous stresses promote survival as well as genetic plasticity. Persistent organisms undergo rapid adaptive evolution, and can function as a reservoir for the elaboration of drug resistance.