Selective Inhibitors of Bacterial DNA Adenine Methyltransferases

Mashhoon, Neda; Pruss, Cynthia M.; Carroll, Michael; Johnson, Paul; Reich, Norbert O.

doi:10.1177/1087057106287933

Cited by 52 publications

(51 citation statements)

References 34 publications

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“…Mutants with deletions of the dam gene lack adenine methylase and are almost uniquely sensitive to TRI. Mashhoon, Reich, and coworkers have identified a number of compounds that specifically inhibit bacterial methylases, including the Dam methylase (58,59). Using these inhibitors in the presence of TRI on the wild-type strain would be equivalent to using a dam mutant strain with TRI and, thus, could be an effective drug combination.…”

Section: Resultsmentioning

confidence: 99%

Antibiotic Sensitivity Profiles Determined with an Escherichia coli Gene Knockout Collection: Generating an Antibiotic Bar Code

Liu¹,

Tran²,

Becket³

et al. 2010

Antimicrob Agents Chemother

262

253

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We have defined a sensitivity profile for 22 antibiotics by extending previous work testing the entire KEIO collection of close to 4,000 single-gene knockouts in Escherichia coli for increased susceptibility to 1 of 14 different antibiotics (ciprofloxacin, rifampin [rifampicin], vancomycin, ampicillin, sulfamethoxazole, gentamicin, metronidazole, streptomycin, fusidic acid, tetracycline, chloramphenicol, nitrofurantoin, erythromycin, and triclosan). We screened one or more subinhibitory concentrations of each antibiotic, generating more than 80,000 data points and allowing a reduction of the entire collection to a set of 283 strains that display significantly increased sensitivity to at least one of the antibiotics. We used this reduced set of strains to determine a profile for eight additional antibiotics (spectinomycin, cephradine, aztreonem, colistin, neomycin, enoxacin, tobramycin, and cefoxitin). The profiles for the 22 antibiotics represent a growing catalog of sensitivity fingerprints that can be separated into two components, multidrug-resistant mutants and those mutants that confer relatively specific sensitivity to the antibiotic or type of antibiotic tested. The latter group can be represented by a set of 20 to 60 strains that can be used for the rapid typing of antibiotics by generating a virtual bar code readout of the specific sensitivities. Taken together, these data reveal the complexity of intrinsic resistance and provide additional targets for the design of codrugs (or combinations of drugs) that potentiate existing antibiotics.

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Section: Resultsmentioning

confidence: 99%

Antibiotic Sensitivity Profiles Determined with an Escherichia coli Gene Knockout Collection: Generating an Antibiotic Bar Code

Liu¹,

Tran²,

Becket³

et al. 2010

Antimicrob Agents Chemother

262

253

View full text Add to dashboard Cite

show abstract

“…A high-throughput small molecule screen identified several lead compounds including those which appear to bind specifically to the allosteric sites of Dam [72]. Some compounds showed greater than 400-fold selectivity for Dam compared to murine DNA cytosine methyltransferase (Dnmt1).…”

Section: Dna Methyltransferasesmentioning

confidence: 99%

DNA Methylation

Marinus

Løbner-Olesen

2014

EcoSal Plus

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The DNA of E. coli contains 19,120 6-methyladenines and 12,045 5-methylcytosines in addition to the four regular bases and these are formed by the postreplicative action of three DNA methyltransferases. The majority of the methylated bases are formed by the Dam and Dcm methyltransferases encoded by the dam (DNA adenine methyltransferase) and dcm (DNA cytosine methyltransferase) genes. Although not essential, Dam methylation is important for strand discrimination during repair of replication errors, controlling the frequency of initiation of chromosome replication at oriC, and regulation of transcription initiation at promoters containing GATC sequences. In contrast, there is no known function for Dcm methylation although Dcm recognition sites constitute sequence motifs for Very Short Patch repair of T/G base mismatches. In certain bacteria (e.g., Vibrio cholerae, Caulobacter crescentus) adenine methylation is essential and in C. crescentus, it is important for temporal gene expression which, in turn, is required for coordinating chromosome initiation, replication and division. In practical terms, Dam and Dcm methylation can inhibit restriction enzyme cleavage; decrease transformation frequency in certain bacteria; decrease the stability of short direct repeats; are necessary for site-directed mutagenesis; and to probe eukaryotic structure and function.

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“…This plethora of virulence-related alterations, combined with the long persistence of dam mutants in infected animals, makes Dam-deficient strains highly suitable as live vaccines (13,14,22). On the other hand, the essential role played by Dam methylation in the virulence of Salmonella and other bacterial pathogens (24) has raised the possibility of using Dam inhibitors as antibacterial drugs (34).…”

mentioning

confidence: 99%

Regulation of the Salmonella enterica std Fimbrial Operon by DNA Adenine Methylation, SeqA, and HdfR

et al. 2008

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DNA adenine methylase (dam) mutants of Salmonella enterica serovar Typhimurium grown under laboratory conditions express the std fimbrial operon, which is tightly repressed in the wild type. Here, we show that uncontrolled production of Std fimbriae in S. enterica serovar Typhimurium dam mutants contributes to attenuation in mice, as indicated by the observation that an stdA dam strain is more competitive than a dam strain upon oral infection. Dam methylation appears to regulate std transcription, rather than std mRNA stability or turnover. A genetic screen for std regulators showed that the GATC-binding protein SeqA directly or indirectly represses std expression, while the poorly characterized yifA gene product serves as an std activator. YifA encodes a putative LysR-like protein and has been renamed HdfR, like its Escherichia coli homolog. Activation of std expression by HdfR is observed only in dam and seqA backgrounds. These data suggest that HdfR directly or indirectly activates std transcription. Since SeqA is unable to bind nonmethylated DNA, it is possible that std operon derepression in dam and seqA mutants may result from unconstrained HdfR-mediated activation of std transcription. Derepression of std in dam and seqA mutants of S. enterica occurs in only a fraction of the bacterial population, suggesting the occurrence of either bistable expression or phase variation.

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Selective Inhibitors of Bacterial DNA Adenine Methyltransferases

Cited by 52 publications

References 34 publications

Antibiotic Sensitivity Profiles Determined with an Escherichia coli Gene Knockout Collection: Generating an Antibiotic Bar Code

Antibiotic Sensitivity Profiles Determined with an Escherichia coli Gene Knockout Collection: Generating an Antibiotic Bar Code

DNA Methylation

Regulation of the Salmonella enterica std Fimbrial Operon by DNA Adenine Methylation, SeqA, and HdfR

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