Microbial Persistence and the Road to Drug Resistance

Abstract

Summary Microbial drug persistence is a widespread phenomenon in which a sub-population 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, non-dividing cells. However, 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, clinically relevant eradication strategies are urgently needed.

Density-dependent adaptive resistance allows swimming bacteria to colonize an antibiotic gradient

“…This finding highlights the importance of adaptive resistance as a route for bacteria to acquire heritable resistance. The hypothesis that adaptively resistant bacteria serve as an evolutionary reservoir from which genotypic mutants may emerge has recently gained ground (Cohen et al, 2013). An antibiotic gradient or the rudimentary version of that-a two patch source-sink systemmay act on such a reservoir and facilitate the evolution of resistance.…”

“…Nonresistant bacteria that are refractory to antibiotic treatment are thought to have an important role in the recalcitrance of bacterial infections (Dhar and McKinney, 2007;Mulcahy et al, 2010;Fauvart et al, 2011;Cohen et al, 2013;Lebeaux et al, 2014). The mechanisms underlying the non-inherited antibiotic refractoriness of bacteria are diverse, and only partially understood (Hogan and Kolter, 2002;Lewis, 2010;Balaban et al, 2013;Orman and Brynildsen, 2013).…”

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

“…These treatment outcomes point to the presence of a subpopulation of T. cruzi parasites in infected mice that do not respond to posaconazole treatment, even though a majority of T. cruzi parasites are killed by the drug. If true, T. cruzi infection could resemble some bacterial infections, such as tuberculosis, in which infected patients are known to harbor bacterial subpopulations that do not respond to treatment with growth inhibitor drugs (36). In the alternative scenario, the treatmentrefractory T. cruzi cells would not have reduced sensitivity to posaconazole but would reside in a tissue(s) poorly penetrated by posaconazole.…”

MazEF toxin-antitoxin proteins alter Escherichia coli cell morphology and infrastructure during persister formation and regrowth

“…Early studies concluded that bacteria exposed to bactericidal antibiotics generate mutagenic reactive oxygen species (ROS), which can damage DNA, creating mutant cells or causing cell death [10,11]. In surviving persister cells, ROS mutagenesis could lead to genetically resistant cells that can grow in the presence of antibiotics [12]. However, other studies have called these conclusions into question [13,14].…”