Bacterial programmed cell death systems as targets for antibiotics

Engelberg‐Kulka, Hanna; Sat, Boaz; Reches, Myriam; Amitai, Shahar; Hazan, Ronen

doi:10.1016/j.tim.2003.12.008

Cited by 170 publications

(163 citation statements)

References 36 publications

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“…Although its role on the E. coli chromosome is not entirely clear, mazEF appears to be a ''stressinduced suicide module'' (55), because it triggers cell death under conditions of amino acid starvation signals (41), antibiotic treatment (56), phage infection (57), thymine starvation (58), oxidative stress, and high temperatures (55). The role of the chromosomally encoded mazEF TA system in E. coli stress response has been reviewed extensively (11,40,55).…”

Section: Discussionmentioning

confidence: 99%

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Toxin–antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci

Moritz¹,

Hergenrother

2007

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

125

127

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Vancomycin-resistant enterococci (VRE) are common hospital pathogens that are resistant to most major classes of antibiotics. The incidence of VRE is increasing rapidly, to the point where over one-quarter of enterococcal infections in intensive care units are now resistant to vancomycin. The exact mechanism by which VRE maintains its plasmid-encoded resistance genes is ill-defined, and novel targets for the treatment of VRE are lacking. In an effort to identify novel protein targets for the treatment of VRE infections, we probed the plasmids obtained from 75 VRE isolates for the presence of toxin-antitoxin (TA) gene systems. Remarkably, genes for one particular TA pair, the mazEF system (originally identified on the Escherichia coli chromosome), were present on plasmids from 75/75 (100%) of the isolates. Furthermore, mazEF was on the same plasmid as vanA in the vast majority of cases (>90%). Plasmid stability tests and RT-PCR raise the possibility that this plasmidencoded mazEF is indeed functional in enterococci. Given this ubiquity of mazEF in VRE and the deleterious activity of the MazF toxin, disruption of mazEF with pharmacological agents is an attractive strategy for tailored antimicrobial therapy.antibiotics ͉ mazEF ͉ axe-txe ͉ relbE ͉ VRE E nterococci are the leading cause of surgical-site infections and the third leading cause of urinary tract and bloodstream infections (1, 2) and are implicated in bacterial endocarditis, intraabdominal infections, bacteremia, and meningitis (3). The intrinsic resistance of enterococci to cephalosporin and aminoglycoside antibiotics complicates treatment strategies. Historically, vancomycin has been effective in the management of enterococcal infections; however, after nearly 30 years of use, vancomycin-resistant enterococci (VRE) emerged in the mid-1980s. In a short time span, intensive care units in the U.S. have seen a dramatic increase in the percentage of enterococcal infections that are resistant to vancomycin, from 0. 4% in 1989 to 25% in 1999 (3). In fact, in a recent study, 60% of Enterococcus faecium clinical isolates were resistant to vancomycin (4).The genes encoding the elaborate protein systems that mediate vancomycin resistance generally reside on mobile genetic elements within the enterococci. In some cases, plasmids with the various vancomycin resistance gene clusters have been recovered from enterococci (5-8), although the prevalence of plasmid-encoded resistance in VRE has not been defined. Large plasmids often have intricate mechanisms by which they maintain themselves in the bacterial population. Some plasmids contain genes encoding postsegregational killing ''plasmid addiction'' systems (9, 10), in which the plasmid encodes a potent toxin and a labile antitoxin. Provided the plasmid is present, the antitoxin binds to and sequesters the toxin. However, if a plasmid-free daughter cell arises, the unstable antitoxin is degraded, and the toxic protein kills the bacterial cell from within.If toxin-antitoxin (TA) systems are prevalent and functional on ...

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Section: Discussionmentioning

confidence: 99%

“…For example, it has been suggested that small molecules that disrupt the TA interaction would free the toxin to kill the host (11)(12)(13). However, both the identity and prevalence of TA systems in pathogenic bacteria are unknown.…”

mentioning

confidence: 99%

Toxin–antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci

Moritz¹,

Hergenrother

2007

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

125

127

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“…The 'toxin/antitoxin immunity' proteins encoded on extra-chromosomal plasmids or viruses of bacteria are considered by many to be a type of 'programmed cell death' in which some members of the population die apparently to provide nutrients to the remaining individuals (Engelberg-Kulka et al, 2004). Thus, this mechanism may allow adjustments in the size of the population to accommodate reduced nutrient supply, perhaps much like that proposed by Kerr et al, 1972, when they coined the term 'apoptosis' to describe the observed reduction in liver size to accommodate the reduced blood supply caused by ligation of the portal vein (Kerr et al, 1972).…”

Section: Programmed Cell Death In Bacteriamentioning

confidence: 99%

Mitochondrial factors with dual roles in death and survival

Berman

Ivanovska

et al. 2006

Oncogene

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At least in mammals, we have some understanding of how caspases facilitate mitochondria-mediated cell death, but the biochemical mechanisms by which other factors promote or inhibit programmed cell death are not understood. Moreover, most of these factors are only studied after treating cells with a death stimulus. A growing body of new evidence suggests that cell death regulators also have 'day jobs' in healthy cells. Even caspases, mitochondrial fission proteins and pro-death Bcl-2 family proteins appear to have normal cellular functions that promote cell survival. Here, we review some of the supporting evidence and stretch beyond the evidence to seek an understanding of the remaining questions.

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“…However, as reported recently, inhibiting the expression of mazEF and thus inducing cell death can be also achieved by several additional stressful conditions. These include the inhibition of transcription and/or translation (35)(36)(37), DNA damage (38,39), and oxidative stress (39).…”

mentioning

confidence: 99%

“…(b) The second direction is studies on the mazEF-mediated cell death network. There is a "point of no return" in MazF-mediated cell death; overexpression of MazE can only reverse MazF lethality over a short window of time (43), suggesting that MazF is a mediator rather than an executioner of cell lethality (44). (c) The third direction is studies on the function of mazEF showing that it can prevent spreading of phage infection (45).…”

mentioning

confidence: 99%

Energetics of Structural Transitions of the Addiction Antitoxin MazE

Lah

Simic

Vesnaver

et al. 2005

Journal of Biological Chemistry

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The Escherichia coli mazEF addiction module plays a crucial role in the cell death program that is triggered under various stress conditions. It codes for the toxin MazF and the antitoxin MazE, which interferes with the lethal action of the toxin. To better understand the role of various conformations of MazE in bacterial life, its order-disorder transitions were monitored by differential scanning calorimetry, spectropolarimetry, and fluorimetry. The changes in spectral and thermodynamic properties accompanying MazE dimer denaturation can be described in terms of a compensating reversible process of the partial folding of the unstructured C-terminal half (high mean net charge, low mean hydrophobicity) and monomerization coupled with the partial unfolding of the structured N-terminal half (low mean net charge, high mean hydrophobicity). At pH < 4.5 and T < 50°C, the unstructured polypeptide chains of the MazE dimer fold into (pre)molten globule-like conformations that thermally stabilize the dimeric form of the protein. The simulation based on the thermodynamic and structural information on various addiction modules suggests that both the conformational adaptability of the dimeric antitoxin form (binding to the toxins and DNA) and the reversible transformation to the more flexible monomeric form are essential for the regulation of bacterial cell life and death.

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Bacterial programmed cell death systems as targets for antibiotics

Cited by 170 publications

References 36 publications

Toxin–antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci

Toxin–antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci

Mitochondrial factors with dual roles in death and survival

Energetics of Structural Transitions of the Addiction Antitoxin MazE

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