Kinase Activity of Overexpressed HipA Is Required for Growth Arrest and Multidrug Tolerance in
            <i>Escherichia coli</i>

Correia, Frederick F.; D’Onofrio, Anthony; Rejtar, Tomáš; Li, Lingyun; Karger, Barry L.; Makarova, Kira S.; Koonin, Eugene V.; Lewis, Kim

doi:10.1128/jb.01237-06

Cited by 182 publications

(180 citation statements)

References 38 publications

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“…The expression of hipA is also able to confer tolerance and increase persister cell formation in response to antibiotic treatment when expressed at low levels (62,134). Although the exact cellular target of HipA remains to be defined, recent evidence demonstrated that HipA belongs to a family of phosphatidylinositide and protein kinases and is capable of autophosphorylation (50). Furthermore, HipA mutant proteins that lack kinase activity were unable to confer antibiotic tolerance, whereas the expression of intact HipA effectively protected cells from antibiotic-induced killing (50).…”

Section: Toxin-antitoxin Systemsmentioning

confidence: 99%

Molecular Control of Bacterial Death and Lysis

Rice

Bayles

2008

Microbiol Mol Biol Rev

320

312

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SUMMARY Although the phenomenon of bacterial cell death and lysis has been studied for over 100 years, the contribution of these important processes to bacterial physiology and development has only recently been recognized. Contemporary study of cell death and lysis in a number of different bacteria has revealed that these processes, once thought of as being passive and unregulated, are actually governed by highly complex regulatory systems. An emerging paradigm in this field suggests that, analogous to programmed cell death in eukaryotes, regulated cell death and lysis in bacteria play an important role in both developmental processes, such as competence and biofilm development, and the elimination of damaged cells, such as those irreversibly injured by environmental or antibiotic stress. Further study in this exciting field of bacterial research may provide new insight into the potential evolutionary link between control of cell death in bacteria and programmed cell death (apoptosis) in eukaryotes.

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Section: Toxin-antitoxin Systemsmentioning

confidence: 99%

Molecular Control of Bacterial Death and Lysis

Rice

Bayles

2008

Microbiol Mol Biol Rev

320

312

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“…Over-expression of this gene may lead to increased generation of persistent cells which could survive antibiotic treatment probably by entering into a dormant state and exhibit multidrug resistance (Correia et al, 2006). WGChl2502-1 encoded a PhoH family protein, which is important to starvation-and stationaryphase-induced resistance to membrane-permeabilizing antimicrobial agents (McLeod and Spector, 1996).…”

Section: Chloramphenicol Resistancementioning

confidence: 99%

Functional metagenomic characterization of antibiotic resistance genes in agricultural soils from China

Wei

et al. 2014

Environment International

151

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“…HipA is a 50-kDa protein, which has a bacterial serine/threonine protein kinase that can phosphorylate the essential translation factor, EF-Tu. Therefore, it has been suggested that HipA places the cell into a dormant state by inhibition of protein synthesis (11,12). The hipA gene is preceded in the operon by the hipB gene, which encodes a 10-kDa protein.…”

Section: Significancementioning

confidence: 99%

Growth feedback as a basis for persister bistability

Feng

Kessler

Ben‐Jacob

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A small fraction of cells in many bacterial populations, called persisters, are much less sensitive to antibiotic treatment than the majority. Persisters are in a dormant metabolic state, even while remaining genetically identical to the actively growing cells. Toxin and antitoxin modules in bacteria are believed to be one possible cause of persistence. A two-gene operon, HipBA, is one of many chromosomally encoded toxin and antitoxin modules in Escherichia coli and the HipA7 allelic variant was the first validated high-persistence mutant. Here, we present a stochastic model that can generate bistability of the HipBA system, via the reciprocal coupling of free HipA to the cellular growth rate. The actively growing state and the dormant state each correspond to a stable state of this model. Fluctuations enable transitions from one to the other. This model is fully in agreement with experimental data obtained with synthetic promoter constructs.A s far back as the 1940s, it was known that a small fraction of a bacterial population can survive even when exposed to prolonged antibiotic treatment (1, 2). This phenomenon is termed persistence and members of the surviving subpopulation are called persisters. It has been estimated that the frequency of persisters in normal wild-type populations is extremely small, perhaps of order 10 −5 ∽10 −6 (3). Although the number of persisters is tiny, they are often the main obstacle to attempts to completely eradicate infection.Remarkably, there is no apparent change in the persisters' DNA sequence; i.e., their survival is not due to mutation (4). Already in 1944, Bigger suggested that persisters are phenotypically different, in a dormant state instead of an actively growing state (1). The dormant state is presumably better able to deal with common antibiotics, which typically target only actively growing cells. Bigger's assumption was confirmed by a later study (3). In this study, Balaban et al. investigated the persistence of a single cell of Escherichia coli by using a microfluidic device. They showed that individual persisters do not always remain in the dormant state. Instead, they stochastically transit into an actively growing state and these newly transited cells are indistinguishable from other normally growing cells. Conversely, normal cells can transit into the persistent state. Thus, bacterial persistence at the population level is governed by a single-cell "phenotypic switch." The precise workings of this switch have to date remained unclear.In the 1980s, Moyed and Bertrand identified the first highpersistence mutant, HipA7, having a persister frequency that is near 10 −2 (4). The discovery of HipA7 facilitated the study of bacterial persistence due to its relatively high proportion of persisters. It was found that HipA7 is formed by a two-residue substitution in the HipA protein. This protein acts as a toxin in a toxin-antitoxin (TA) module (5, 6), where the hipB gene is coexpressed with hipA and the corresponding protein binds to and neutralizes HipA toxicity. To da...

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Kinase Activity of Overexpressed HipA Is Required for Growth Arrest and Multidrug Tolerance in Escherichia coli

Cited by 182 publications

References 38 publications

Molecular Control of Bacterial Death and Lysis

Molecular Control of Bacterial Death and Lysis

Functional metagenomic characterization of antibiotic resistance genes in agricultural soils from China

Growth feedback as a basis for persister bistability

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