Nucleic Acids Research Advance Access published online on November 28, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn936
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bacterial topoisomerase I as a target for discovery of antibacterial compounds
Yuk-Ching Tse-Dinh*
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
*To whom correspondence should be addressed. Tel: +1 914 594 4061; Fax: +1 914 594 4058; Email: yuk-ching_tse-dinh{at}nymc.edu
Received October 1, 2008. Revised November 5, 2008. Accepted November 5, 2008.
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ABSTRACT
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Bacterial topoisomerase I is a potential target for discovery
of new antibacterial compounds. Mutant topoisomerases identified
by SOS induction screening demonstrated that accumulation of
the DNA cleavage complex formed by type IA topoisomerases is
bactericidal. Characterization of these mutants of
Yersinia pestis and
Escherichia coli topoisomerase I showed that DNA
religation can be inhibited while maintaining DNA cleavage activity
by decreasing the binding affinity of Mg(II) ions. This can
be accomplished either by mutation of the TOPRIM motif involved
directly in Mg(II) binding or by altering the charge distribution
of the active site region. Besides being used to elucidate the
key elements for the control of the cleavage-religation equilibrium,
the SOS-inducing mutants of
Y. pestis and
E. coli topoisomerase
I have also been utilized as models to study the cellular response
following the accumulation of bacterial topoisomerase I cleavage
complex. Bacterial topoisomerase I is required for preventing
hypernegative supercoiling of DNA during transcription. It plays
an important role in transcription of stress genes during bacterial
stress response. Topoisomerase I targeting poisons may be particularly
effective when the bacterial pathogen is responding to host
defense, or in the presence of other antibiotics that induce
the bacterial stress response.
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INTRODUCTION
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Topoisomerases catalyze the interconversion of DNA topological
isomers via coupling of DNA phosphodiester bond cleavage and
religation with the passage of DNA through the break. By maintaining
global DNA supercoiling at optimal level and removing local
topological barriers, DNA topoisomerases play vital roles in
DNA replication, transcription, repair and recombination (
1).
Topoisomerases are divided into different subfamilies based
on their mechanisms and sequence similarities (
2–4). Type
I topoisomerases cleave and rejoin one strand of DNA while type
II topoisomerases cleave and rejoin a double strand of DNA during
catalysis. Human topo IB, IIA and bacterial topo IIA enzymes
are well utilized clinical targets for anticancer and antibacterial
chemotherapy (
5–9). These topoisomerase targeting compounds
initiate the cell killing process by either stabilizing or increasing
the accumulation of the covalent complex formed between the
enzyme and cleaved DNA and are called ‘topoisomerase poisons’
(
9–11). Compounds that interact with type IA topoisomerases
with high specificity to increase the level of the covalent
complex remain to be identified. The emergence of bacterial
pathogens resistant to multiple antibacterial drugs in both
the hospital and community setting is a serious global public
health problem, presenting an urgent need for discovery of new
classes of antibacterial compounds. Based on the similarities
in the topoisomerase mechanisms, it should be productive to
identify small molecules that can act as poisons of bacterial
type IA topoisomerases.
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TYPE IA TOPOISOMERASES BACTERIA
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There is at least one type IA topoisomerase found in each bacterial
genome (
12). Topo I is present in all bacteria and is the major
activity responsible for removal of excess negative supercoiling
(
13). In
Escherichia coli, the promoters of topo I and gyrase
genes are under homeostatic control by DNA supercoiling to maintain
the global level of supercoiling (
14,
15). Topo III is found
in only some of the bacterial genomes.
In vitro it is much more
efficient in catalyzing DNA decatenation reaction than relaxation
(
13).
Escherichia coli topo III has been proposed to play a
role in resolving RecQ associated recombination intermediates
(
16). Transposon insertion or deletion mutants in the
topA gene
coding for topo I could be isolated from
E. coli, Salmonella typhimurium and
Shigella flexneri (
17–20). Attempts to
isolate transposon insertion mutants in the
topA gene were unsuccessful
in
Mycobacterium tuberculosis and
Helicobacter pylori (
21,
22)
suggesting that topo I might be essential in these bacteria.
This should be further investigated by additional genetic studies.
In
E. coli, topo III is also not essential but absence of both
type IA topoisomerases resulted in chromosomal segregation defect
(
23). It was proposed that a type IA topoisomerase activity
is required in general for resolving recombination intermediates
involving single strand DNA passage (
1). A broad spectrum type
IA topoisomerase poison that can act on both topo I and topo
III would have a target always present in any bacteria.
Even though E. coli topA mutants are viable, growth at low temperature requires topo I function (24,25). During transcription, the movement of the RNA polymerase complex generates positive supercoils in the DNA template ahead of it and negative supercoils behind it (26). Topo I activity is needed for removal of the negative supercoils to prevent hypernegative supercoiling and R-loop formation (27,28). The importance of topo I function in transcription is also illustrated by the direct protein–protein interaction between E. coli topo I and RNA polymerase (29,30).
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FUNCTION OF BACTERIAL TOPOISOMERASE I IN STRESS RESPONSE AND PATHOGENESIS
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The role of topo I in relaxation of transcription-induced negative
supercoiling is probably especially important during stress
response when a large number of stress genes have to be induced
rapidly for survival (
31). Transcription of
E. coli topA gene
is under control of multiple promoters recognized by
32,
38
in addition to
70 (
32,
33). Besides these alternative
factors,
topA transcription is also regulated by binding of Fis to the
promoter region (
34). Topo I function and regulation have been
shown to be important for
E. coli response to high temperature
and oxidative stress (
35–38). RNase H overproduction can
partially restore the
32–dependent stress genes transcription
defect in the absence of
topA, indicating that R-loop formation
from hypernegative supercoiling at heat shock genes loci is
responsible for the effect of the
topA mutation. The response
to high temperature and oxidative stress is an important element
of bacterial pathogen adaptation against host defense. In
H. pylori, the
topA gene has been shown to be up-regulated by prolonged
acid exposure (
39). Loss of topo I function in
E. coli affects
transcription of the acid resistance genes
gadA and
gadBC involving
a mechanism independent of R-loop suppression (
40). It was shown
recently that a pathway of
38 stress response involves unwrapping
of the poised inactive transcription complex by DNA relaxation
to allow activation (
41). The relaxing activity of topo I may
play a role via this mechanism in the activation of some of
the promoters that are stimulated by DNA relaxation (
42,
43).
The important role of topo I in bacterial stress response and
pathogenesis implies that if topo I activity is reduced as a
defensive adaptation for an antibiotic acting as type IA topoisomerase
poison, the ability of the pathogen to survive in the host environment
may be compromised.
Bacterial genes related to pathogenesis and virulence have been shown to be sensitive to topA mutation. These include the fooB gene for fimbriae F1651 in pathogenic E. coli 4787 (44) and the thermally regulated invasive genes of S. flexneri (20). The invA gene of S. typhimurium was poorly expressed in a topA mutant, and this correlated with the ability of S. typhimurium to penetrate tissue culture cells (45). Signature-tagged transposon mutagenesis has identified topA to be one of the genes affecting survival of Yersinia enterocolitica in animal host (46). In addition, topA gene was among those found to be highly expressed by avian pathogenic E. coli (APEC) in infected tissues (47).
The lethal mechanism of many bactericidal antibiotics based on different mechanisms of action, including quinolones and ampicillin, have been shown to involve at least in part the formation of reactive oxygen species (48–50). Since bacteria in general would respond to such antibacterial antibiotics with transcription of stress regulons, topo I is expected to interact extensively with negatively supercoiled DNA at the induced transcription loci, and provide additional opportunity for the topo I cleavage complex to be trapped by an inhibitor. Topo I inhibitors that act as poisons may therefore be particularly effective in combination therapy with other antibiotics.
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CELL KILLING BY BACTERIAL TOPOISOMERASE I MUTANTS THAT ACCUMULATE THE COVALENT CLEAVAGE COMPLEX
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Since molecules that can act effectively as bacterial topo I
poisons have not been previously identified, it is important
to demonstrate that trapping of topo I cleavage complexes on
single-stranded DNA will indeed lead to bacterial cell death,
just as tapping of type IIA topoisomerases on double-stranded
DNA would. This would validate the targeting of bacterial topo
I in the search for novel antibacterial compounds. It is known
from previous work that the SOS response of
E. coli is induced
by the trapping of gyrase cleavage complex by quinolones (
51).
Topo I mutations that mimic the action of a topoisomerase poison
and result in increased accumulation of the cleavage complex
may be expected to also induce the SOS response. The isolation
of such topo I mutants was achieved by screening for SOS-inducing
recombinant mutant
Yersinia pestis topo I expressed in
E. coli under the control of the tightly-regulated BAD promoter (
52).
A pool of mutagenized plasmid pYTOP expressing random mutants
of
Y. pestis topo I was first isolated in the presence of 2%
glucose to suppress the expression of any potentially lethal
mutant that accumulate the cleavage complex. The mutagenized
plasmid was then transformed into
E. coli JD5 strain with
dinD1::
lacZ fusion. Induction of the DNA damage SOS response would result
in synthesis of β-galactosidase from activation of the
dinD1 promoter and formation of blue colonies on Xgal plate.
SOS-inducing
Y. pestis topo I mutants were identified in such
blue colonies in the presence of low concentration of arabinose
to activate the BAD promoter. Induction of an SOS-inducing mutant
topo I with high concentration of arabinose resulted in
4 logs
loss of viable counts after 2 h (
52). The mutation responsible
for this phenotype was identified to be a Gly to Ser substitution
in the TOPRIM motif DxDxxG conserved in nucleotidyl transferases
(
53). Mutant topoisomerase with this Gly to Ser substitution
was found to be defective in DNA rejoining after formation of
the covalent DNA cleavage complex (
52). This result demonstrated
that accumulation of the covalent cleavage complex of bacterial
topo I could indeed lead to rapid bacterial cell death and validated
bacterial type IA topoisomerases as useful targets for discovery
of novel bactericidal compounds. The Gly to Ser mutation was
the only substitution found at that position to have the SOS-inducing
and cell killing phenotypes for
Y. pestis topo I. The other
more bulky substitutions eliminated DNA cleavage activity. A
Met to Val substitution immediately following the active site
tyrosine was present in the original SOS inducing mutant (
52)
and was found to enhance DNA cleavage without inhibiting DNA
religation (
54).
Mg2+ ions are required for DNA rejoining and DNA relaxation by type IA topoisomerases (13,55). The aspartates in the TOPRIM motif DxDxxG in E. coli topo I have been shown to coordinate two Mg2+ ions (56). Mg2+ binding by the TOPRIM motif is found to be critical for the DNA cleavage-religation equilibrium of bacterial topo I. Characterization of the SOS-inducing and cell killing topo I mutants demonstrated that there are at least three mechanisms of decreasing Mg2+ binding affinity and inhibiting DNA religation (Figure 1). The Gly to Ser mutation at the TOPRIM motif probably distorted the structure of the TOPRIM domain as the first mechanism of perturbing DNA cleavage-religation. Replacement of the conserved Met adjacent to the active site tyrosine with Arg also resulted in reduced Mg2+ binding, inhibition of DNA religation and the cell killing phenotype. Molecular modeling was in agreement with increased positive charge in the active site region due to the substitution of the neutral Met with the positively charged Arg (57). The change in electrostatic potential in the active site provided a second mechanism of perturbing Mg2+ binding and DNA cleavage-religation. It is also expected that interfering with the metal-ligand interaction directly would provide a third mechanism of perturbing Mg2+ binding and DNA cleavage-religation. Results from our recent experiments showed that an Asn substitution at the first TOPRIM motif Asp residue gave rise to an extremely toxic topo I mutant, and the Asn substitution at the second TOPRIM motif Asp residue also resulted in a mutant that was lethal when induced (B. Cheng et al., manuscript in preparation).
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Figure 1. Structure of the 67 kDa N-terminal fragment of E. coli topo I (PDB ECL1) and the close-up view of the active site showing the nucleophilic tyrosine Y319 and the residues in the TOPRIM motif and active site region where mutations can result in cell killing due to inhibition of Mg2+ binding and DNA religation.
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While the involvement of Mg
2+ ions is widely found in many cellular
catalytic mechanisms, there is precedence for small molecules
affecting Mg
2+ interactions being identified as specific inhibitors
of a cellular process which have been approved in human therapy.
HIV-1 integrase is an important new target for anti-viral therapy
for cases resistant to existing drugs against HIV-1 reverse
transcrptase and protease (
58,
59). The integrase mechanism is
similar to the type IA topoisomerase mechanism in the use of
two aspartates and one glutamate (
56) to coordinate two divalent
ions and bring about protein conformational change (
60–62).
Small molecules that can chelate the divalent ions in the HIV-1
integrase active site have been identified and one, raltegravir
has been approved for treatment of AIDS patients (
63,
64). Therefore
it is not unreasonable to expect that it may be possible to
inhibit the interaction between bacterial topo I and metal ions
in the active site with a small molecule and achieve accumulation
of the DNA cleavage complex for antibacterial therapy.
While the TOPRIM motif and surrounding residues around the active site tyrosine (Figure 1) have been identified to be important for controlling DNA cleavage/religation, other regions of the bacterial topo I protein could also affect the level of accumulation of the covalent cleavage complex. Subdomain III with the 5'phosphate of the cleaved DNA bound covalently to the active site tyrosine needs to separate from subdomains I and IV as the enzyme transitioned from the closed structure (Figure 1) to a more open structure during the catalytic cycle for DNA strand passage to take place. Subdomain I then must move back to near its original position before DNA religation can occur. Mutations or small molecules that can stabilize the intermediate complex with subdomain III separated from subdomains I and IV by affecting the protein conformational changes could also lead to increased accumulation of the cleavage complex in vivo and result in cell killing. It is hopeful that further characterization of the SOS-inducing topo I mutants would identify regions in the topo I structure that may be potential binding sites for such small molecules.
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CELLULAR RESPONSE TO TOPOISOMERASE I CLEAVAGE COMPLEX AND THE CELL DEATH PATHWAY
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The bacterial topo I mutants that accumulate the cleavage complexes
were utilized to study the cellular response to topo I cleavage
complex and the repair pathway in
E. coli. The homologous recombination
function of RecA was found to be required for repair of topo
I cleavage complex. Induction of the SOS response by the recombination
deficient RecA718 protein was found to be insufficient for repair
of topo I mediated DNA cleavage (
65) Quinolones are known to
induce the SOS response of
E. coli via the RecBCD pathway (
66).
Double-strand DNA breaks and chromosomal fragmentation occur
after trapping of the cleavage complex between the gyrase A
subunits and both strands of DNA (
67,
68). Although topo I cleaves
only a single-strand of DNA at a time, RecBCD function was also
found to be required for induction of the SOS response by RecA
(
65). The
E. coli RecBCD complex unwinds and degrades DNA at
double strand breaks with free DNA ends until the RecBCD activity
is modified by encountering a Chi site on DNA. The Chi-modified
RecBCD nuclease activity generates a 3' single-stranded overhang
and facilitates the assembly of a RecA filament on this single-stranded
DNA region downstream of the Chi site (
69). Mutations in the
single-strand gap repair pathway genes
recF and
recR were found
to have no effect on SOS induction or viable colony counts following
accumulation of the topo I cleavage complex (
65). It remains
to be determined how the single strand break covalently linked
to topo I protein is converted to a double strand break with
free ends that can be processed by the RecBCD complex.
The quinolone induced gyrase cleavage complex blocks DNA replication, but ongoing DNA replication is not necessary or sufficient for the lethal effect of the quinolones (11,70). Depending on the structure of the quinolone, inhibition of protein synthesis following quinolone addition by chloramphenicol may or may not offer protection. This suggests that there is more than one pathway involved for the lethal action of quinolones (11). It is possible that a newly synthesized protein may be required for one of the cell killing pathways. In eukaryotes, Tyr-DNA phosphodiesterase (Tdp1) activity has been shown to cleave the linkage between 3' DNA phosphate and type IB topoisomerases (71,72), and may in addition also be involved in the processing of the type IIA topoisomerases linked to the 5' DNA phosphate (73,74). Homologues of Tdp1 have not been identified in bacterial genomes so it is not known if a bacterial Tyr-DNA phosphodiesterase is available to cleave the linkage between the type IA and type IIA topoisomerase proteins and the 5' phosphates of the cleaved bacterial DNA.
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INHIBITORS OF BACTERIAL TOPOISOEMRASE I
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Even though DNA gyrase is the primary target of quinolones in
E. coli, certain quinolones including perfloxacin, ciprofloxacin,
norfloxacin and ofloxacin have been shown to inhibit the relaxation
activity of
E. coli topo I at concentrations 10-fold or higher
of that required to inhibit the supercoiling activity of
E. coli gyrase (
75,
76). Nevertheless,
E. coli topo I was found
to be significantly more sensitive to these quinolones than
calf thymus topoisomerase I and II.
Inhibition of E. coli topo I by phospholipids has also been reported (77). The inhibition of the in vitro relaxation activity by cardiolipin (Figure 2A) could be suppressed by chlorpromazine. Treatment of E. coli cells with chlorpromazine resulted in relaxation of plasmid DNA that was dependent on the function of the topA gene. This suggested that chlorpromazine may interfere with the in vivo interaction between E. coli topo I and phospholipids in E. coli cells (77).
Escherichia coli Tn5 transposase protein has been shown to copurify
with
E. coli topo I and inhibit its relaxation activity (
78).
The titration of topo I activity by overexpressed Tn5 transposase
leads to filamentation, aberrant nucleoid segregation and cell
death (
79). The lethality from overexpression of Tn5 transposase
could be suppressed by chromosomal mutations that increased
the level of topo I protein (
80). The N-terminal amino acids
of Tn5 transposase are required for the interaction with topo
I and the resulting lethal effect from Tn5 transposase overexpression
(
78,
79).
In order to identify small molecules as leads for bacterial topo I poisons, a cell based high-throughput assay was developed utilizing E. coli cells with enhanced permeability to small molecules, and overexpressing Y. pestis topo I with the dinD1::luxCADBE luciferase fusion as reporter (81). The goal was to identify small molecules that could induce higher level of SOS response when wild-type recombinant topo I was overexpressed as compared to the recombinant topo I with the active site nucleophile tyrosine residue substituted with alanine. Three small molecules (Figure 2B) capable of enhancing bacterial topo I DNA cleavage and inhibiting the relaxation activity have been identified (81). These compounds had antibacterial activity against the gram positive Bacillus subtilis but not E. coli cells with normal permeability, and may not have the desired specificity against bacterial topo I (81). Compound 1 is the natural product stephenanthrine, a phenanthrene alkaloid. It has structural similarities to benzo[c]phenanthridines and protoberberine alkaloids that have been shown to enhance the DNA cleavage of mammalian topoisomerase I and II (82). Minor groove binders including the bisbenzimide Hoechst 33342 are known to exhibit anti-tumor activity due to inhibition of human topoisomerase I and trapping of the human topoisomerase I cleavage complex (83). More recently, modification of Hoechst 33342 has provided novel ligands that could clear bacterial infections from mammalian cell culture without apparent cytotoxicity to the mammalian cells, and these ligands preferentially inhibited E. coli topo I over human topo I in vitro (Vibha Tandon, personal communications). These results suggest that modification of ligand structures can potentially shift their specificity from inhibiting mammalian topoisomerase I towards targeting bacterial topo I, improving their antimicrobial potential while limiting the cytotoxicity.
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FUTURE DIRECTIONS
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Additional screenings should be carried out to identify compounds
that can act as topo I poisons so that they can be developed
into leads for new antibacterial therapy. Two high-throughput
assays have been developed assaying DNA supercoiling by DNA
gyrase and DNA relaxation by eukaryotic topo I and II as well
as
E. coli topo IV (
84). These assays should be applicable to
identifying small molecules that can inhibit relaxation by bacterial
topo I. Some of the relaxation inhibitors may act by inhibiting
DNA religation and be useful as a bacterial topo I poison. Other
in vitro high-throughput assays that can directly measure the
level of the topo I cleavage complex would be extremely useful
for identifying new leads.
With sites in bacterial topo I structure important for the control of the DNA cleavage-religation equilibrium being located by the SOS-inducing mutations, it should be possible to identify small molecules that can interact with these sites in the enzyme. The virtual screening approach has been used to discover novel gyrase inhibitors (85), and should be attempted for identifying leads for discovery of bacterial topo I poisons.
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FUNDING
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National Institutes of Health (R01-GM54226, R01-AI6933). Funding
to pay the Open Access publication charges for this article
was provided by R01-AI69313.
Conflict of interest statement. none declared.
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ACKNOWLEDGEMENTS
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I thank Dr. Bernard I. Weinstein for comments on the manuscript.
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