Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy

Grimwade, Julia E.; Leonard, Alan C.

doi:10.3390/antibiotics8030111

Cited by 11 publications

(9 citation statements)

References 143 publications

(232 reference statements)

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“…While transcriptional modulators clearly play a key role in regulating E. coli origin function during the cell cycle, far less is known about other bacterial types. There are clearly transcriptional regulators that bind to other bacterial origins and regulate initiation; these include CtrA, SpoOA, AdpA, and MtrA in C. crescentus , B. subtilis , S. coelicolor , and M. tuberculosis , respectively, reviewed in ( Wolanski et al, 2014 ; Grimwade and Leonard, 2019 ). However, for the most part, how precise initiation timing is achieved in most bacterial types is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Blocking, Bending, and Binding: Regulation of Initiation of Chromosome Replication During the Escherichia coli Cell Cycle by Transcriptional Modulators That Interact With Origin DNA

Grimwade

Leonard

2021

Front. Microbiol.

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Genome duplication is a critical event in the reproduction cycle of every cell. Because all daughter cells must inherit a complete genome, chromosome replication is tightly regulated, with multiple mechanisms focused on controlling when chromosome replication begins during the cell cycle. In bacteria, chromosome duplication starts when nucleoprotein complexes, termed orisomes, unwind replication origin (oriC) DNA and recruit proteins needed to build new replication forks. Functional orisomes comprise the conserved initiator protein, DnaA, bound to a set of high and low affinity recognition sites in oriC. Orisomes must be assembled each cell cycle. In Escherichia coli, the organism in which orisome assembly has been most thoroughly examined, the process starts with DnaA binding to high affinity sites after chromosome duplication is initiated, and orisome assembly is completed immediately before the next initiation event, when DnaA interacts with oriC’s lower affinity sites, coincident with origin unwinding. A host of regulators, including several transcriptional modulators, targets low affinity DnaA-oriC interactions, exerting their effects by DNA bending, blocking access to recognition sites, and/or facilitating binding of DnaA to both DNA and itself. In this review, we focus on orisome assembly in E. coli. We identify three known transcriptional modulators, SeqA, Fis (factor for inversion stimulation), and IHF (integration host factor), that are not essential for initiation, but which interact directly with E. coli oriC to regulate orisome assembly and replication initiation timing. These regulators function by blocking sites (SeqA) and bending oriC DNA (Fis and IHF) to inhibit or facilitate cooperative low affinity DnaA binding. We also examine how the growth rate regulation of Fis levels might modulate IHF and DnaA binding to oriC under a variety of nutritional conditions. Combined, the regulatory mechanisms mediated by transcriptional modulators help ensure that at all growth rates, bacterial chromosome replication begins once, and only once, per cell cycle.

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Section: Discussionmentioning

confidence: 99%

Blocking, Bending, and Binding: Regulation of Initiation of Chromosome Replication During the Escherichia coli Cell Cycle by Transcriptional Modulators That Interact With Origin DNA

Grimwade

Leonard

2021

Front. Microbiol.

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“…Given their opposing roles in DNA replication, it is possible that partially inhibiting both proteins would counteract the effects of inhibiting each individually. Nevertheless, mistimed DNA replication can clearly lead to bacterial cell death ( 28 ), and inhibition of multiple proteins involved in the initiation of DNA synthesis could lead to complex lethal effects.…”

Section: Resultsmentioning

confidence: 99%

Essential Paralogous Proteins as Potential Antibiotic Multitargets in Escherichia coli

Hardy¹

2022

Microbiol Spectr

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“…Based on the current knowledge concerning bacterial persister formation under different physiological stress conditions, several anti-persister strategies have already been proposed ( Defraine et al., 2018 ). A promising therapy that emerges from our discussion could involve the inhibition of the bacteria-specific error-prone repair enzymes, especially of the Y-family TLS polymerases, by specific inhibitors ( Yamanaka et al., 2017 ; Ketkar et al., 2019 ) to prevent mutations possibly also leading to ABR, and - after the antibiotic treatment - the inactivation of DnaA to prevent re-initiation of DNA replication and cell division of the generated persisters ( Makise et al., 2002 ; Schenk et al., 2017 ; Samadpour and Merrikh, 2018 ; Grimwade and Leonard, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Link Between Antibiotic Persistence and Antibiotic Resistance in Bacterial Pathogens

Eisenreich

Rudel

Heesemann

et al. 2022

Front. Cell. Infect. Microbiol.

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Both, antibiotic persistence and antibiotic resistance characterize phenotypes of survival in which a bacterial cell becomes insensitive to one (or even) more antibiotic(s). However, the molecular basis for these two antibiotic-tolerant phenotypes is fundamentally different. Whereas antibiotic resistance is genetically determined and hence represents a rather stable phenotype, antibiotic persistence marks a transient physiological state triggered by various stress-inducing conditions that switches back to the original antibiotic sensitive state once the environmental situation improves. The molecular basics of antibiotic resistance are in principle well understood. This is not the case for antibiotic persistence. Under all culture conditions, there is a stochastically formed, subpopulation of persister cells in bacterial populations, the size of which depends on the culture conditions. The proportion of persisters in a bacterial population increases under different stress conditions, including treatment with bactericidal antibiotics (BCAs). Various models have been proposed to explain the formation of persistence in bacteria. We recently hypothesized that all physiological culture conditions leading to persistence converge in the inability of the bacteria to re-initiate a new round of DNA replication caused by an insufficient level of the initiator complex ATP-DnaA and hence by the lack of formation of a functional orisome. Here, we extend this hypothesis by proposing that in this persistence state the bacteria become more susceptible to mutation-based antibiotic resistance provided they are equipped with error-prone DNA repair functions. This is - in our opinion - in particular the case when such bacterial populations are exposed to BCAs.

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Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy

Cited by 11 publications

References 143 publications

Blocking, Bending, and Binding: Regulation of Initiation of Chromosome Replication During the Escherichia coli Cell Cycle by Transcriptional Modulators That Interact With Origin DNA

Blocking, Bending, and Binding: Regulation of Initiation of Chromosome Replication During the Escherichia coli Cell Cycle by Transcriptional Modulators That Interact With Origin DNA

Essential Paralogous Proteins as Potential Antibiotic Multitargets in Escherichia coli

Link Between Antibiotic Persistence and Antibiotic Resistance in Bacterial Pathogens

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