Effects of persister formation on bacterial response to dosing

Abstract

Almost all moist surfaces are colonized by microbial biofilms. Biofilms are implicated in cross-contamination of food products, biofouling and various human infections such as dental cavities, ulcerative colitis and chronic respiratory infections. The recalcitrance of biofilms to typical antibiotic and antimicrobial treatments is one focus of current investigations. Neither reaction-diffusion limitation nor heterogeneities in growth-rate explain the observed tolerance. Another hypothesis is that specialized 'persister' cells, which are extremely tolerant of antimicrobials, are the source of resistance.In this investigation, we describe the formation of 'persister' cells which neither grow nor die in the presence of antibiotics. We propose that these cells are of a different phenotype whose expression is regulated by the growth rate and the antibiotic concentration. Based on several experiments describing the dynamics of persister cells, we introduce a mathematical model that is used to describes the effect of a periodic dosing regiment. Results from our analysis indicate that the relative dose/withdrawal times are important in determining the effectiveness of such a treatment. A reduced model is also introduced and the similar behavior is demonstrated analytically.

Senescence can explain microbial persistence

“…Balaban et al, 2004;Cogan, 2006;Kussell et al, 2005;Roberts & Stewart, 2005;Sufya et al, 2003;Wiuff et al, 2005), that is, that persisters are cells with the same genome but with different sets of genetic expression than 'normal' cells, and that a given cell can switch back and forth between the two states.…”

“…Balaban et al (2004), Roberts & Stewart (2005) and Cogan (2006) have proposed models in which cells are able to switch in and out of a protected, slow-or non-growing persister state with probabilities that are dependent possibly on environmental conditions. In this paper, based on observations of microbial senescence (Ackermann et al, 2003;Barker & Walmsley, 1999;Mortimer & Johnston, 1959;Stewart et al, 2005), we instead propose an alternative simple mechanism that can explain all of the above-mentioned properties.…”

The role of small-colony variants in failure to diagnose and treat biofilm infections in orthopedics

“…Biofilm bacteria may produce persister cells that neither grow nor die in the presence of antibiotics (Cogan 2006). Persister cells are largely responsible for the high levels of tolerance to antibiotics seen in biofilms (Lewis 2005), but the environmental stimuli that turn on the switch to the persister phenotype are poorly understood.…”

“…In these regions, although normal cells are unable to grow, they slowly switch to the persister phenotype. Cogan (2006) suggested that expression of persister cells is controlled by the growth rate and the antibiotic concentration. Persister cells can be regarded as specialized survivor cells.…”

Failure of antibiotic treatment in microbial populations

“…Many of these mechanisms depend on whether the bacteria exist in a biofilm or not [8,10,13,9]. In particular, the notion that small sub-populations of bacteria may display innate tolerance to various biocides has been proposed as a possible reason for the failure of treatment for bacterial infections [16,2,14,5]. Bacteria within a biofilm are enmeshed in a physical gel that provides a secondary boundary that may allow small numbers of bacteria to evade the antibiotic; therefore, the failure to eliminate the entire population can allow the population to regrow.…”