Metabolic Control of Persister Formation in Escherichia coli

Amato, Stephanie M.; Orman, Mehmet A.; Brynildsen, Mark P.

doi:10.1016/j.molcel.2013.04.002

Cited by 326 publications

(363 citation statements)

References 62 publications

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“…3d). Factors such as quorum sensing, cell density, nutrient starvation, diauxic carbon source transitions, environmental signals (such as heat shock, oxidative stress and DNA damage) and stringent response pathways contribute to microbial persistence in vitro [54][55][56][57][58][59] . TA modules that are upregulated in persisters are terminal effectors of microbial persistence 60,61 .…”

Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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Toxin-antitoxin (TA) systems are highly conserved in members of the Mycobacterium tuberculosis (Mtb) complex and have been proposed to play an important role in physiology and virulence. Nine of these TA systems belong to the mazEF family, encoding the intracellular MazF toxin and its antitoxin, MazE. By overexpressing each of the nine putative MazF homologues in Mycobacterium bovis BCG, here we show that Rv1102c (MazF3), Rv1991c (MazF6) and Rv2801c (MazF9) induce bacteriostasis. The construction of various single-, double-and triple-mutant Mtb strains reveals that these MazF ribonucleases contribute synergistically to the ability of Mtb to adapt to conditions such as oxidative stress, nutrient depletion and drug exposure. Moreover, guinea pigs infected with the triple-mutant strain exhibits significantly reduced bacterial loads and pathological damage in infected tissues in comparison with parental strain-infected guinea pigs. The present study highlights the importance of MazF ribonucleases in Mtb stress adaptation, drug tolerance and virulence.

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Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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“…More recent studies have begun to revise this view with the demonstration that even non-, or slowly, replicating bacteria could be rendered sensitive to antibiotics. Studies of Escherichia coli, Staphylococcus aureus and even Mtb have shown that the activity of many antibiotics: (i) is dependent on the activity of specific metabolic pathways, (ii) differs for replicating and nonreplicating populations and (iii) can be dissociated from growth rate 7,12,27 . In Mtb, it was shown that adaptation to hypoxia was accompanied by a redirection of metabolic flux away from the TCA cycle and towards the generation of triglycerides, whose inhibition resensitized Mtb to antibiotics in absence of growth 7 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent work has expanded the scope of physiologic factors associated with antibiotic resistance to include broader bacterial stress responses, such as the SOS DNA stress response, heatshock response and oxidative stress response, as well as changes in metabolic state and activity [7][8][9][10][11][12] . These antibiotic-induced responses then contribute functionally to resistance.…”

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confidence: 99%

Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis

2014

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Mycobacterium tuberculosis (Mtb) is a persistent intracellular pathogen intrinsically tolerant to most antibiotics. However, the specific factors that mediate this tolerance remain incompletely defined. Here we apply metabolomic profiling to discover a common set of metabolic changes associated with the activities of three clinically used tuberculosis drugs, isoniazid, rifampicin and streptomycin. Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant. These results identify a previously undescribed role for Mtb's ICLs in antioxidant defense as a mechanism of antibiotic tolerance.

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“…The stringent response is a highly conserved mechanism that enables bacteria (1)(2)(3) and plant chloroplasts (4)(5)(6) to respond to nutrient (i.e., amino acid) limitations. However, recent work has indicated that guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) [collectively named "(p)ppGpp"] also impact other, nonstringent response processes such as virulence (7)(8)(9) as well as persister (10,11) and biofilm formation (12). Realization of the importance of (p)ppGpp has also opened new avenues for the design of antimicrobial agents (13,14).…”

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confidence: 99%

Catalytic mechanism and allosteric regulation of an oligomeric (p)ppGpp synthetase by an alarmone

Steinchen

Schuhmacher

Altegoer

et al. 2015

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

112

172

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Nucleotide-based second messengers serve in the response of living organisms to environmental changes. In bacteria and plant chloroplasts, guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) [collectively named "(p)ppGpp"] act as alarmones that globally reprogram cellular physiology during various stress conditions. Enzymes of the RelA/SpoT homology (RSH) family synthesize (p)ppGpp by transferring pyrophosphate from ATP to GDP or GTP. Little is known about the catalytic mechanism and regulation of alarmone synthesis. It also is unclear whether ppGpp and pppGpp execute different functions. Here, we unravel the mechanism and allosteric regulation of the highly cooperative alarmone synthetase small alarmone synthetase 1 (SAS1) from Bacillus subtilis. We determine that the catalytic pathway of (p)ppGpp synthesis involves a sequentially ordered substrate binding, activation of ATP in a strained conformation, and transfer of pyrophosphate through a nucleophilic substitution (S N 2) reaction. We show that pppGpp-but not ppGpp-positively regulates SAS1 at an allosteric site. Although the physiological significance remains to be elucidated, we establish the structural and mechanistic basis for a biological activity in which ppGpp and pppGpp execute different functional roles. stringent response | (p)ppGpp | hydrogen-deuterium exchange mass spectrometry | alarmone | crystallography T he ability of living organisms to adapt their metabolism to nutrient limitation or environmental changes is of utmost importance to survival. The stringent response is a highly conserved mechanism that enables bacteria (1-3) and plant chloroplasts (4-6) to respond to nutrient (i.e., amino acid) limitations. However, recent work has indicated that guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) [collectively named "(p)ppGpp"] also impact other, nonstringent response processes such as virulence (7-9) as well as persister (10, 11) and biofilm formation (12). Realization of the importance of (p)ppGpp has also opened new avenues for the design of antimicrobial agents (13,14).Central to these processes is the synthesis of two alarmones, pppGpp and ppGpp, which globally reprogram the transcription and translation associated with a variety of cellular processes (summarized in refs. 9 and 15) and which also control the elongation of DNA replication (16). Until now, both alarmones have been collectively named "(p)ppGpp," because knowledge of their individual roles remained mysterious. Only recently has a study indicated that either alarmone might execute disparate biological functions (17).Alarmone synthesis is carried out by synthetases of RelA/SpoT homology (RSH) (18) that catalyze the transfer of pyrophosphate (β-, γ-phosphates) from ATP to the ribose 3′-OH of GDP or GTP to synthesize ppGpp or pppGpp, respectively. An in-depth analysis of the catalytic mechanism for this reaction is currently not available. Only one structure describes the GDP-bound state of an RSH synthetase domain, bearing remarkable simil...

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Metabolic Control of Persister Formation in Escherichia coli

Cited by 326 publications

References 62 publications

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis

Catalytic mechanism and allosteric regulation of an oligomeric (p)ppGpp synthetase by an alarmone

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