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Food Control
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a r t i c l e i n f o
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Article history:
Received 9 March 2012
Received in revised form
23 May 2012
Accepted 1 June 2012
We review early work on the microbial growth curve and the concept of balanced growth followed by
commentary on the stringent response and persister cells. There is a voluminous literature on the effect
of antibiotics on resistance and persistence and we call for a greater focus in food microbiology on the
effect of biocides in the same context. We also raise potential issues in development of resistance arising
from sourceesink dynamics and from horizontal gene transfer. Redox potential is identied as crucial
in determining microbial survival or death, and the recently postulated role for reactive oxygen species in
signalling also considered.
Traditional predictive microbiology is revisited with emphasis on temperature dependence. We
interpret the temperature vs growth rate curve as comprising 11 regions, some well-recognised but
others leading to new insights into physiological responses. In particular we are intrigued by a major
disruption in the monotonic rate of inactivation at a temperature, slightly below the actual maximum
temperature for growth. This non-intuitive behaviour was earlier reported by other research groups and
here we propose that it results from a rapid metabolic switch from the relaxed growth state to the
stringent survival state.
Finally, we envision the future of predictive microbiology in which models morph from empirical to
mechanistic underpinned by microbial physiology and bioinformatics to grow into Systems Biology.
2012 Elsevier Ltd. All rights reserved.
Keywords:
Predictive microbiology
Systems biology
Biological rates
Stringent response
Persister cells
Antibiotic-resistance
Biocide-resistance
Sourceesink
Growth rate etemperature response
Bioinformatics
Protein-folding-thermodynamics
Mechanistic model
1. Introduction
This paper is based on a presentation of the same title given at
7ICPMF in September 2011 (McMeekin, Olley, Ratkowsky, & Ross,
2011). In the presentation we discussed rates and time scales in
microbiology, early studies on microbial growth rate curves and the
concept of balanced growth. This was followed by consideration of
the stringent response and persister cells, topics which are underrepresented in the food microbiology literature. Attention was then
focused on modelling studies with emphasis on temperature
dependence models. Finally, we asked if the quantitative information embedded in predictive models could be effectively integrated
with microbial physiology and omics technologies.
In answer to the question posed in the presentation title, . is it
all about rates? we were condent to respond positively when the
question addressed the use of predictive models to estimate the
safety and shelf-life of foods. However, our response was equivocal
when the question was framed in the context of integrating
predictive models with microbial physiology studies and the data
deluge emanating from omics studies. Here we extend the scope
* Corresponding author.
E-mail address: tom.mcmeekin@utas.edu.au (T. McMeekin).
0956-7135/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.foodcont.2012.06.001
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rate to a zero net growth rate. Despite that the lag and stationary
phases of growth are regions of zero or very slow growth they are
crucial to the continuation of a lineage as will be evident when the
physiology of the stringent response and of persister cells are
considered. The physiology of the lag phase identies it as a distinct
growth phase that prepares cells for exponential growth (Rolfe
et al., 2012).
3. The stringent response e paradigm lost in food
microbiology
Even major changes in the physiology of the cell can occur in
seconds. A good example is the transition from the relaxed
response state to that of the stringent response and the converse
switch which occur in 20e30 s (Cashel, 1975). This is equivalent to
the half lives of guanosine tetraphosphate (ppGpp) and guanosine
pentaphosphate (ppGppp), the alarmones that give an unequivocal
clue to cells to switch from one state to the other (Lund &
Kjeldgaard, 1972). Thus, in a few seconds the purpose of cellular
metabolism is totally reversed from a focus on growth (the relaxed
state) to a focus on survival (the stringent [response] state; SR).
The SR has been shown to play a signicant role in processes as
different as biolm formation, quorum sensing, antibiotic resistance, and virulence regulation (Navarro Llorens, Tormo, &
Martinez-Garcia, 2010). Perhaps, it also provides an explanation
for the Jameson Effect? Here we posit that the component of
a mixed culture to approach MPD rst produces sufcient ppGpp
not only to signal its entry into the SR state but also that of its
competitors. Relief from the SR state can be achieved by inoculation
into a fresh batch culture or prevented by growth in continuous
cultures in which the alarmone is continually diluted and nutrients
are continually added. However, if a continuous culture is set up in
a retentostat (a chemostat with 100% feedback of biomass) very
slow or zero growth rates ensue (Chesbro, Evans, & Eifert, 1979;
Gofn et al., 2010). This phenomenon can again be attributed to the
programmed objective of the stringent response physiological
state: survival at any cost. During transition from the exponential to
the stationary phase the cytoplasmic concentration of the general
stress factor (RpoS) increases in Gram negative cells (Gentry et al.,
2003; Lange & Hengge Aronis, 1991, 1994) and cell density and
quorum sensing compounds have been proposed to have a role in
the mechanism of transition (Hengge-Aronis, 2002). However,
Ihssen and Egli (2004) argued that, as other factors (growth rate,
carbon source availability and metabolite concentration) also
change during the transition, quorum sensing alone is insufcient
to explain the transition. They concluded, on the basis of both batch
and continuous culture experiments, that RpoS expression is not
controlled by quorum sensing, that specic growth rate plays
a prominent role and that ppGpp is a possible intracellular signal
linking RpoS and specic growth rate. From an ecological standpoint this egoistic strategy of self-determination by individual
cells was deemed to be eminently sensible compared with the
more risky option of depending on signals from other cells. The line
of reasoning developed by Ihssen and Egli (2004) was supported by
Potrykus, Murphy, Philippe, and Cashel (2011) who concluded that
ppGpp is the major source of growth rate control in Escherichia coli.
4. Persister cells e stealth bombers in the microbial
survival armoury?
Cells with slow or zero growth rates confer a very distinct
competitive advantage on microbial populations that, as a result of
minimal metabolism, are extremely difcult to inactivate. The term,
bacterial persistence, was introduced by Bigger (1944) who reported the inability of ampicillin to sterilize cultures of
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293
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295
- The value of Tmin is xed and does not depend on other environmental variables such as water activity or pH. However,
MINt values vary markedly depending on other factors;
- A constant Tmin value provides a convenient way to construct
a relative rate curve, the basis of technologies to predict the
microbiological safety and stability of foods;
- There is a continuum of Tmin values describing the thermal
adaptation of bacteria across all temperature categories, psychrophiles, psychrotropes*, mesophiles and thermophiles;
- A constant Tmin leads to a simple multiplicative model to
describe the combined effect of several hurdles (the Gamma
hypothesis);
- The form of the model suggests that the combined effect of
several hurdles is additive and not synergistic when the cells
are growing;
- Synergisitic effects occur at the growth/no growth interface
and beyond when cell physiology switches from growth to
survival mode;
- The gap between Tmin and MINt increases with progressively
harsher conditions due to energy diversion to deal with additional hurdles.
(*n.b., The term psychrotroph has gained almost universal approval
in the food microbiology literature to describe a cold tolerant
microorganism but the etymology of the word is incorrect as
etroph, from which psychrotroph is derived is a sufx referring to
nourishment. The correct sufx to indicate cold tolerant is etrope
or etropic referring to turning, as in heliotrope or geotropic).
9. The elements of a growth rate versus temperature plot for
the full biokinetic temperature range
The response of growth rate to temperature plotted as
the square root of growth rate versus temperature is shown in
Fig. 1. This has the advantage of homogenising the variance and
Fig. 1. Typical plot of the square root of the specic growth rate constant vs.
temperature. 1. Tmin e theoretical minimum temperature for growth; 2. MINt e actual
minimum temperature for growth; 2e3. Region of variability in growth rate estimates
due to the distribution of long response times; 4e5. Region of maximum enzyme
stability surrounding Tmes, the point of maximum enzyme stability (Ratkowsky et al.,
2005); 6. Point at which the rate of increase of the specic growth rate starts to
decline; 7. Point at which the maximum specic growth rate is reached. Growth rate
estimates are variable around this temperature; 8. Start of monotonic decline in
growth rate; 9e10. Region in which monotonic decline is disrupted and inactivation
occurs; 10. MAXt e actual maximum temperature for growth; 11. Tmax e theoretical
maximum temperature permitting growth.
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